Melanoma_Missionary

“I have your results”..Melanoma..Jim Breitfeller

2012-02-01T07:25:00.002-05:00

Tuesday, Jan 31, 2012 3:00 PM 17:47:41 EST

“I have your results”

Mary Elizabeth Williams is a staff writer for Salon

Three months into a draining clinical trial, the doctor called with news. Was it working -- or not?
I had just settled into a chair for my regular Tuesday night cancer support group when I got the call. An unfamiliar number. A split second of wondering whether or not to answer. And then my doctor, calling from his own phone to say, “I have your results.”

People with metastatic, Stage 4 melanoma rarely get happy endings. They usually just get endings. The odds of surviving five years once the cancer has spread into your lungs and bloodstream are generally ballparked at around 10 percent. So when I entered a Phase I immunotherapy clinical trial in October, I knew the whole enterprise had the pungent aroma of Last Ditch. My doctors said brightly that my relative youth and good health made me “an ideal candidate.” They said that the drug combination I’d be on – the newly approved Ipilimumab and the experimental, sexily named MDX-1106 – were highly “promising.” Because it was a trial, Bristol-Myers Squibb would essentially foot the bill. They had also just told me that the malignant cancer I had surgery for in 2010 had broken off; there was now a tumor in my lung and another one under the flesh of my back. In the stark absence of other options, I signed a 27-page consent form alerting me to potential side effects from diarrhea to hepatitis and even death. And with that, I started on a protocol that I hoped wouldn’t kill me before the cancer did.
Every three weeks, I spend a day on the fourth floor at Memorial Sloan-Kettering, hooked up to an IV as strange new drugs drip into my system. Every week, I am monitored and quizzed and examined and have truly ludicrous amounts of blood drawn. The external effects of the regimen presented themselves early on – crushing exhaustion, an itchy rash, dizzy spells – but I would have to wait three months, until January, to learn whether the drug combo was doing any real work on my cancer. The fact that the lump on my back subsided after the very first treatment was encouraging enough to get my doctor enthusing, but having been declared “cancer free” once before, I knew to temper optimism with caution. Especially because these are uncharted waters.

Immunotherapy, my doctor says, is like religion. “For years,” he tells me, “we just had to go on faith.” It differs radically from chemo in that it coaxes your body’s own defenses to attack disease – and then, astonishingly, to continue defending the body after treatment has ended. It’s still considered a new frontier in cancer care, and at first glance, it’s easy to see why. Its main forerunner is Interleukin-2, an immune-system treatment for patients with metastatic cancer that is infrequently used and only sporadically effective. And one of the immunotherapy drugs I’m on, Ipilimumab, won FDA approval last year with a mere 30 percent success rate.
Yet the way we treat – and try to head off – cancer is changing radically. Look no further than the rise of the vaccine Gardasil. Since its approval in 2006, it has been routinely given to girls to help ward off HPV, which can cause cervical cancer. And just last week, the Roswell Park Cancer Institute in Buffalo launched a Phase 1 clinical trial for a vaccine researchers say “harnesses the power of the body’s immune system to kill cancer cells.” Imagine a world in which preventing and treating cancer didn’t automatically mean harsh protocols like chemo, radiation or interferon. Imagine something that might someday be as simple as getting a shot. It’s coming. Because as my clinical trial nurse puts it, “It’s the immune system, stupid.”
That dramatic day, however, is still a long way off. In the meantime, if the other 10 people doing this trial at MSKCC are anything like me, they’ve been dealing with scarred veins, side effects and nagging uncertainty. Science may be moving at a breathtaking clip, but when you’ve got a cancer that often kills within a year, it simply may not be moving quickly enough for all of us.
That’s why when my doctor said he had my results, I wasn’t sure I wanted to know. I had been at MSKCC just that morning, guzzling sickly sweet, room-temperature liquid and holding my breath inside the CT scan machine. After three months of infusions, I’d now know whether that spot in my lung was growing or shrinking, whether my cancer was accelerating or diminishing. That night, as I stood in the hall outside my support group, I held my breath again. And then my doctor told me, “I have good news.”

“The tumor in your lungs is gone,” he continued, “and the one on your back has receded completely.” I don’t know a lot of fancy medical jargon, but I do know that “good news,” “gone” and “receded completely” are, for a person with distant metastases, downright extraordinary.
Two days later, I was back at Sloan-Kettering, awaiting my next infusion. “I know you can’t reveal much,” I’d asked, “but can you say anything about how the other people in the trial are doing?” I may be thriving, but if it turned out other patients were dropping like flies, I’d hold off on popping a bottle of Dom.
“We had two other patients who had scans this week,” the doctor said. “Both of their tumors have shrunk significantly. But you’re at 100 percent, so that makes you our valedictorian.” And while it’s nice to be valedictorian, what it really means to a team of researchers — and Bristol-Myers Squibb — is that I am solid results.
This isn’t a happy ending. People with Stage 4 cancer don’t really get those. This isn’t even an ending. I’m still only halfway through a trial that is kicking my ass. After I complete it in March, I will be on maintenance treatment every three months for the next two years. I will have skin checks and MRIs and scans for the rest of my life. I live with the reality that melanoma, as I have already learned firsthand, makes more comebacks than Cher. And nobody really knows for sure what the long-term effects of my treatment are, because nobody’s ever done this particular course before. I’m hoping they include super strength and sexual charisma, but liver damage seems likelier.

Yet right now, I have hope that the middle-aged woman in Treatment Suite 26, the one whose elderly father sits by her side as they watch “Dr. Phil” together, is getting better. That the tall, 20-something guy in the Superman T-shirt, a genial fellow who tells me the cancer has already come back twice before, is too. And it’s a humbling and fantastic thing to consider that, someday, because of what the sick and the healers are doing on the fourth floor, you might get to survive, too.

When I went in for my last treatment, my doctor asked if I wanted to see my scans. You bet I did. He sidled over to a monitor in the corner of the exam room and brought up an image dated Oct. 6, 2011. “This is your lung,” he said. “See that there? That blob? That’s the tumor.” Then he brought up another image right next to it. “This is you now.” It looked just the other one, but with one significant difference. No blob. He did the same for the picture of my back. “Here’s the cancer,” he said. There was a green arrow pointing to it, a flag that some technician added three months ago, a little signpost of malignancy. “And this,” he said, double-clicking on a different picture, “is you now. Nothing.” Nothing has never looked so beautiful.

“Wow,” I replied. “That’s amazing.”
“Yeah, it is,” he said, beaming. “It’s more fun when it works.” I looked at the monitor and smiled too. Within those weird, abstract images I could see so much, so clearly. I could see sunsets and birthday parties; I could see snowmen and sand castles. And I thought, yup, it’s the best fun ever. It’s even better than a happy ending. It’s a future.

Immunotherapy + Cancer Vaccines will be the future.

In my next post I will show you how we can beat cancer (Melanoma) with combinational therapy. This is so new that your Oncologists don't even know about. It is the culmination of the last 5 years of my my search for a cure.

“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”
~Charles Darwin~
Take Care,
Jimmy B

New Perspectives On Cancer And The Immune System..Melanoma. Jim Breitfeller

2012-01-31T13:52:00.005-05:00

BY AMEILIA, ON MARCH 27TH, 2011

In a new review article published in yesterday’s special section of Science focusing on the past forty years since the U.S. declared “War on Cancer,” three Cancer Research Institute scientists describe how advances in the field of tumor immunology have revealed a complex and paradoxical relationship between cancer and the immune system, and discuss how a growing understanding of this relationship is providing a scientific foundation for new therapies capable of unleashing the immune system’s protective powers against cancer.
Several recent breakthroughs in cancer treatment are based in immunological principles described in the review. These include Provenge® (sipuleucel-T), a dendritic cell vaccine that received FDA approval in April 2009 for the treatment of advanced, hormone-refractory prostate cancer, the successful monoclonal antibodies Herceptin® and Rituxan® approved in the 1990s for the treatment of breast cancer and non-Hodgkin’s lymphoma, emerging therapeutic cancer vaccines, and new treatment strategies that combine standard chemotherapy and radiation therapy with investigational cancer immunotherapies. The review places these treatment advances within a scientific context spanning a century of laboratory and clinical effort aimed at learning how to direct the power of the immune system to fight cancer.
Authors Robert D. Schreiber, Ph.D., at the Washington University School of Medicine in St. Louis, MO; Lloyd J. Old, M.D., at the Ludwig Institute for Cancer Research at Memorial Sloan-Kettering Cancer Center in New York, NY; and Mark J. Smyth, Ph.D., at the Peter MacCallum Cancer Centre and University of Melbourne in Melbourne, Australia, describe in their review how fundamental discoveries made over the past forty years reveal that the immune system plays a dual role in protecting against cancer and in promoting cancer growth. Taken together, these insights support a unifying conceptual framework they call “cancer immunoediting.”

“The cancer immunoediting paradigm succeeds in answering a number of questions that have eluded tumor immunologists for decades, such as why tumors can sometimes lie dormant in patients for years before re-emerging, and why tumors grow despite evidence that they provoke an immune response,” says Schreiber. “It also provides a platform for improving current cancer treatments and developing new therapeutic strategies that aim to interfere with or reverse phases of the immunoediting process that contribute to tumor growth.”
During cancer immunoediting, the immune system is able to recognize and attack the most immunologically vulnerable cancer cells, i.e. those cancer cells that clearly appear dangerous to the immune system because they display molecular markers, called antigens, that identify them as damaged, secrete chemicals associated with dysfunctional cellular activity, or otherwise behave in ways the immune system recognizes to be dangerous. Schreiber, Old, and colleagues have called this first phase of cancer immunoediting the “elimination” phase.

“It has long been thought that elimination is occurring all the time in healthy hosts,” says Schreiber, “where the immune system is able to destroy nascent cancerous cells before they can develop into tumors.” This process has not yet been observed directly in living animals or humans, but has been inferred by the presence of tumor-specific immune cells and antibodies found in cancer patients.

In the second phase of cancer immunoediting, called “equilibrium,” surviving cancer cells continue to divide rapidly, accumulating mutational changes by chance or in response to immunological pressures that enable tumors to impair the immune system’s ability to eliminate them. Rather, a balance between immune control and tumor growth is maintained, giving the appearance of tumor dormancy.

Over time, however, cancer cells can continue to undergo sculpting by the immune system and eventually enter into the third and final phase, “escape.” During the escape phase, tumor cells that have acquired the ability to circumvent immune recognition and/or destruction emerge as progressively growing, visible tumors. The switch from equilibrium to escape can be caused either by changes in the tumor cells in response to the immune system’s editing functions, or because the immune system changes in response to increased cancer-induced immunosuppression or immune system deterioration.

The ability of cancers to evade immune attack has recently been accepted as one of the key defining characteristics, or hallmarks, of cancer, as described in a recent paper from Hanahan and Weinberg published earlier this month in Cell. How cancer evades the immune system is still a topic of intense research, as Schreiber, Old, and Smyth describe in their review.
“Some cancer cells stop signaling danger to the immune system through loss of the ability to process and present surface markers that help identify them to the immune system,” says Old. Without signals that differentiate them from normal cells, these cancer cells become “invisible” to the immune system.

Another channel for tumor escape is opened when cancer cells establish an immunosuppressive state within the tumor microenvironment. According to Old, tumor cells initiate a process involving a complex network of regulatory cells and molecules that can effectively shut down immune recognition and control of the tumor. This process normally functions to prevent the dangers of autoimmunity, a state where the immune system attacks and destroys normal cells of the body.

A key immune cell involved in inhibiting immune responses in both tumor immunity and autoimmunity is the regulatory T cell. Studies of tumors infiltrated with immune cells have demonstrated a clear relationship between the ratio of regulatory cells to effector, or cell-killing, immune cells and overall patient prognosis, with those having fewer regulatory cells faring better than patients whose tumors are more immunosuppressive.

According to the paper’s authors, to be effective, cancer immunotherapies will have to increase the quality or quantity of immune cells capable of eliminating cancer cells, reveal additional protective tumor antigens, and/or eliminate cancer-induced immunosuppression. Multiple forms of immunotherapy are being explored to achieve these objectives, including therapeutic cancer vaccines, adoptive transfer of tumor-specific immune cells, monoclonal antibodies that target cancer cells for elimination, and approaches that inhibit or destroy molecular or cellular mediators of cancer-induced immunosuppression.

“Indeed, the interface between conventional approaches such as surgery, radiotherapy, standard, and new small molecule targeted chemotherapies (e.g. Gleevec®, kinase and B-raf inhibitors) and all of these new immunotherapeutic approaches is extremely exciting,” Smyth says. “It will prove a special challenge for institutions, pharmaceutical companies, and regulatory authorities alike to rationally deliver these combinations to cancer patients in a timely way.”
“After a long and controversial history, immunological approaches to the control and treatment of cancer are now established on a firm experimental foundation,” says Old. “Advances in the field of cancer immunology, from the definition of cancer antigens to the understanding and control of cancer related immunosuppression, are pointing the way to a new era in cancer therapy based on the specificity and power of the immune system.”

The authors point to future work in cancer immunoediting that will address questions like: which components of the immune system play a role in each of the three phases of cancer immunoediting and how, what are the specific differences between tumor antigens on immunoedited cells compared to unedited tumors, is it possible to predict how a tumor will be immunoedited based on the types of antigens that are expressed, is a durable state of immune equilibrium a desirable and attainable endpoint for cancer immunotherapy, and how can we most effectively inhibit cancer-induced immunosuppression at the tumor site without inducing autoimmunity?

Finding answers to each of these important questions will provide tumor immunologists with further insights needed to optimize immunotherapies for use in treating cancer patients.
In 2007, the Schreiber, Old, and Smyth jointly received the Charles Rodolphe Brupbacher Prize for Cancer Research for their joint and complementary contributions to the field of cancer immunology and, particularly, to a better understanding of the concepts of cancer immunosurveillance and immunoediting. The three scientists also received the Cancer Research Institute William B. Coley Award for Distinguished Research in Basic and Tumor Immunology: Old (1975), Schreiber (2001), and Smyth Smyth (2002).

Source: Cancer Research Institute

“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”

~Charles Darwin~
Take Care,

Jimmy B

Using Immunohistologic Characteristics of Tumor Infiltrating Immune Cells to the advantage of Melanoma Patients.Jim Breitfeller

2012-01-30T10:28:00.013-05:00

In the research paper “Immunotype and Immunohistologic Characteristics of Tumor Infiltrating Immune Cells are Associated with Clinical Outcome in Metastatic Melanoma”1 et al Slingluff 2012, it breaks down the Immunohistologic Characteristics into three distinct immunotypes:

A) No infiltration of immune cells in the tumor’s microenvironment.
B) Infiltrating Immune cells only in close proximity to the tumor’s vascular system
C) Diffuse immune cell infiltrates throughout a metastatic tumor and its microenvironment.

Overall, the most predominant immune cells were T cells (53%), followed by the B cell lineage cells (33%), and then by macrophages (13%), with NK and mature dendritic cells only hardly present.

With the setting of the tumor’s microenvironment evaluated, we will focus the low survival immunotype A patients. How can we improve the overall survival and the immune response to Melanoma?

Here are just some of the therapies we have to date:

Dacarbazine (FDA approved)
High Dose Interluekin-2 (FDA approved)
Yervoy (Anti-CTLA-4) (FDA approved)
Zelboraf (Braf inhibitor) (FDA approved)

These therapies work well in a subset of melanoma patients but the overall survival rates are still quite low. We need to somehow combine these immunotherapies with a cancer vaccine to invoke an immune response with memories T-cells so we can eliminate any reoccurrence.
Oncologists have been working on this for decades.

I believe they may have discovered the right combination to just that. Dr. Kingston Mills and colleagues from the Immune Regulation Research Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin
Immunotherapy with PI3K Inhibitor and Toll-Like Receptor
Agonist Induces IFN-g þIL-17þ Polyfunctional T Cells That
Mediate Rejection of Murine Tumors

Neil A. Marshall1, Karen C. Galvin1, Anna-Maria B. Corcoran1, Louis Boon3,
Rowan Higgs2, and Kingston H.G. Mills1,2

Authors' Affiliations: 1Immune Regulation Research Group, School of
Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity
College Dublin, Dublin, Ireland; 2Immunology Research Centre, Trinity
Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland; and
3Bioceros, Utrecht, The Netherlands

Dr. Mills and colleagues discovered that if you combine a PI3k inhibitor with TRL agonists (TRL-9 and or 5) with DC vaccine/tumor antigen, you invoke a tremendous immune response along with memory cells.

This combination actually tilts the T-cell differentiation towards the Th1 phenotype that is needed to activate the CD8+ T-cells. I believe this is a major breakthrough toward curing/stabilizing the Melanoma Cancer.

The immune activation by CpG ODN +(PI3k inhibitor) initiates with specific binding to the TLR-9 receptor in B cells and plasmacytoid DCs. TLR-9 ligation in DCs results in secondary activation of lymphocytes, macrophage, monocyte, NK-cell, and T-cell populations through the elaboration of cytokines generating a Th1 cytokine milieu. This results in increased NK activity as well as improved antigen presentation and T cell help that can augment
humoral and cell-mediated immune responses. In addition, TLR ligation results in the production of IL-6 by DCs, which helps overcome the suppressive effect of CD4 CD25 Treg cells.

We must break the tolerance to generate immune responses against the tumor antigens.

This combination developes a population of polyfunctional T-cells that produce interferon-gamma and IL-17, both potent mediators of the immune response. Moreover, the combination has a lasting effect. This combination also produces the “Danger Signal” that is needed to recruit the immune cells to the tumor’s microenvironment.

A fledgling startup company (Trimod Therapeutics) holds the patent to this technology.

Dr. Jeremy Skillington
http://www.trimodtherapeutics.com/

As stated in my previous post, we need a cancer vaccine with Anti-CTLA-4 and IL-2 to produce a lasting immune response. I believe this company holds the future of immunotherapy cure/stabilization for Melanoma and maybe more cancers. Only time will tell with the right Clinical protcol in place. This is years away, but holds a temendous promise due to the science behind it. We need to expidite this rationale for the good of the Cancer patients.

“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”
~Charles Darwin~

Take Care,
Jimmy B

CTLA-4 Blockade with Ipilimumab: Long-Term Follow-up of 177 Patients with Metastatic Melanoma ..Jim Breitfeller

2012-01-29T19:37:00.003-05:00

Peter A Prieto, James C. Yang, Richard M. Sherry, Marybeth S. Hughes, Udai S. Kammula, Donald E White, Catherine L Levy, Steven A. Rosenberg, and Giao Q Phan
Clin Cancer Res clincanres.1823.2011;

Published Online First January 23, 2012

Abstract

Purpose: Treatment with ipilimumab can cause objective tumor responses in patients with metastatic melanoma. We have treated 177 evaluable patients in three clinical trials and have long-term follow-up to evaluate the durability of responses. Patients and Methods: Patients with metastatic melanoma were treated in three trials from 2002 to 2005: In Protocol 1, fifty-six patients received ipilimumab with gp100 peptides. In Protocol 2, thirty-six patients received ipilimumab with interleukin-2. In Protocol 3, eighty-five patients received ipilimumab with intra-patient dose escalation and were randomized to receive gp100 peptides. We have analyzed their long-term follow-up and survival data. Results: With median follow-up for Protocols 1, 2, and 3 being 92, 84, and 71 months, median survival was 14, 16, and 13 months with five-year survival being 13%, 25%, and 23%, respectively. Patients in Protocol 2 had a 17% complete response (CR) rate, compared to 7% in Protocol 1 and 6% in Protocol 3. These CR rates are higher than previously reported for the same trials because some patients who eventually became CRs had continual tumor regression months to years after therapy. All but one of the 15 complete responders are ongoing at 54+ to 99+ months. Conclusions: This report provides the longest follow-up of melanoma patients treated with ipilimumab and shows that ipilimumab can induce durable, potentially curative tumor regression in a small percentage of patients with metastatic melanoma.

The combination of ipilimumab and IL-2 appears to have an increased (CR)Complete Response rate, but this needs to be tested in a randomized trial.

If you have been following me on Carepage and or Melanoma Missionary, we knew about this combination back in 2009. I have been pushing for this trial. I even wrote and posted an email to Dr. Steven A. Rosenberg on 3/29/2009 at NCI.

"To summarize, Timing and Doses of both Anti-CTLA-4 and IL-2 can have a major effect on the immune response outcome. If you follow the dosing and timing regime, I postulate that you will see a synergist outcome with this combination therapy."

Jimmy B ..3/29/2009

I have learned a lot through my researched and still believe that my systematic combination theory of Anti-CTLA-4 and IL-2 still holds water. In fact as we speak, I am reseaching the tumor's microenviroment to see how we can improve on this response rate. How the tumor operates in the neighborhood of cells. How it changes the neighborhood with Cytokines, Tregs and cell to cell contact. It is simular to having one bad apple in the basket and how it causes other bad apples.

And By adding Cancer Vaccines to this combination, I believe we can CURE Melanoma.

Best Regards,

Jimmy B

“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”

~Charles Darwin~

Take Care,

Jimmy B

Cancer immunotherapy comes of Age,,Melanoma..Jim Breitfeller

2012-01-11T14:31:00.003-05:00

Author:Ira Mellman1, George Coukos2 & Glenn Dranoff3

Nature:4 8 0 | NATURE | VOL 480 | 22/29 DECEMBER 2011

"Activating the immune system for therapeutic benefit in cancer has long been a goal in immunology and oncology. After decades of disappointment, the tide has finally changed due to the success of recent proof-of concept clinical trials. Most notable has been the ability of the anti-CTLA4 antibody, ipilimumab, to achieve a significant increase in survival for patients with metastatic melanoma, for which conventional therapies have failed. In the context of advances in the understanding of how tolerance, immunity and immunosuppression regulate antitumour immune responses together with the advent of targeted therapies, these successes suggest durable and long-lasting response in cancer patients."

We as patients of the Clinical trials are right in the middle of this awakening!!!!

Here is the article:

Cancer immunotherapy comes of age

“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”
~Charles Darwin~
Take Care,
Jimmy B

Holiday Wishes to you All !! Melanoma..Jim Breitfeller

2011-12-25T12:27:00.003-05:00

I would like to wish each and every one of my carepage friends the warmest and deepest greetings this Holiday Season. We been through a lot and with the comfort of family and friends we can beat the Beast Melanoma.

It has been truely a renewed emergence in Melanoma therapy this past year with TWO therapies being FDA approved that extends survival for us Melanoma patients. At this time of the Season, please relect on the Worriors that are no longer with us, but made this all possible by offering their life to the progress of science.

They truely have shown us the gift of giving.

They truely are my/our HEROS!!!

We will miss them dearly.

Happy Holidays

“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”

~Charles Darwin~

Take Care,

Jimmy B

'Pep talk' can revive exhausted immune cells: Study..Melanoma..Jim Breitfeller

2011-12-14T11:17:00.001-05:00

'Pep talk' can revive exhausted immune cells: Study
Published: Wednesday, Dec 14, 2011, 14:33 IST
Place: Washington, DC | Agency: IANS

'Pep talk' can revive exhausted immune cells

Exhaused immune cells can be revived by blocking the receptors PD-1 on the The CD8+ T-cells. By reviving the immune cells (CD8+), one can jump start the immune system and may be able to recognize the Melanoma tumors. There are now a number of clinical trials with this therapy in mind.

“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”

~Charles Darwin~

Take Care,

Jimmy B

Lloyd J. Old, Champion of Using Cells to Fight Cancer, Dies at 78..Melanoma..Jim Breitfeller

2011-12-05T15:53:00.001-05:00

Lloyd J. Old, Champion of Using Cells to Fight Cancer, Dies at 78

My theory on how the immune system works on Melanoma had it's starts with papers from Dr. Lloyd Old.

Lloyd J. Old, Champion of Using Cells to Fight Cancer

“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”

~Charles Darwin~
Take Care,

Jimmy B

Why Does Yervoy need to be systematically combined with IL-2? Melanoma..Jim Breitfeller

2011-10-20T11:41:00.004-04:00

Yervoy therapy acts upon the T-cells by blocking the CTLA-4 receptor, making it unable to engage. By doing this blockade, the CD28/B7 complex can engage and the signaling to activate, secrete and multiply is allowed. Cytokines produced by activated cells can stimulate or inhibit the production of other cytokines by the same cells in an autocrine manner or those present in the vicinity by a paracrine mechanism. Thus, a complex network of cell interactions is established, with positive and negative feedback controls, regulating cytokine production. For example,
TNF-a induces the synthesis of both IL-1 and IL-6 in macrophages. In contrast, IL-10, which is also synthesized by macrophages, inhibits the synthesis of TNF-a, IL-1 and IL-6. Both IFN-g and TNF-a can activate macrophages, which subsequently synthesize TNF-a and IL-1. What I am trying to elude to is that depending on the microenvironment which contains many cytokines, the pattern of cytokines matters whether the macrophages are activated or not.

This does not take into account the suppressiveness of the Tumor’s activity. Melanoma tumors can secrete TGF-b and IL-10 and other suppressive molecules. These suppressive cytokines (IL-10) can block the activation of the tumor associated macrophages (TAMs) which in turn inhibits the secretion of other cytokines and chemoattractants into the Tumor’s microenvironment. This inhibition suppresses the “Danger Signal” needed to alarm the immune system of foreign invaders (Tumor cells).
Th1 cells promote macrophage activation by producing IL-2 and IFN-g. What if the Th1 cells are not producing enough or there are many Tregs in the tumor’s microenvironment recruited by the tumors themselves? The Tregs, Th1 and the CD8+ T-cells are all competing for the IL-2 for survival. There could be a shortage of IL-2 to satisfy all the cells leading to a less than robust response. It has been greatly accepted that macrophage activation by IL-2 is essential for tumor regression. et al Masztalerz
So administration of HD IL-2 during the peak propagation of the (ALC) Absolute Lymphocyte Count (7 weeks or 49 days) may be synergetic to Yervoy.

“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”

~Charles Darwin~
Take Care,

Jimmy B

Identifying and Over Coming Immune Barriers at the Level of the Tumor Microenvironment..Melanoma .Jim Breitfeller

2011-10-14T12:08:00.009-04:00

Eleventh International Conference on Progress in Vaccination Against Cancer

Dr. Thomas Gajewski
University of Chicago,Chicago,IL,USA

"Immunotherapeutic approaches for the treatment of melanoma, such as tumor antigen-based vaccines, can frequently boost immune responses. However, clinical responses as measured by tumor shrinkage are seen in only a minority of patients. This observation has prompted careful analysis of the tumor microenvironment for biologic correlates to clinical response and also to identify mechanisms of tumor resistance. Patients with advanced melanoma treated with antigen-specific vaccines had pre-treatment tumor biopsies analyzed by gene expression profiling. Supervised hierarchical clustering was performed based on clinical outcome. An expanded bank of tumors was analyzed to increase the sample size and better understand gene patterns.
Two major categories of melanoma metastases have been observed.

One subgroup of patient has an inflamed phenotype that includes expression of chemokines, T-cell markers, and other immunoregulatory factors. Clinical responders to melanoma vaccines appear to fall within this subset. This group also contains the highest expression of negative regulatory factors, including PD-L1, IDO, and FoxP3, suggesting that these immunosuppressive mechanisms may dominantly inhibit anti-tumor –cell function in those patients. In addition, absence of B7 expression supports classical T-cell anergy. Preclinical experiments have confirmed a critical role for these mechanisms in limiting anti-tumor T–cell efficacy in vivo, giving candidate treatment strategies for translation back into the clinic.

A second subset of patients is represented by tumors which are non-inflamed and lack chemokines for T cell recruitment. Therefore, a major barrier in these cases appears to be failed T –cell migration into tumor sites. Experimental strategies to augment T-cell migration can have important anti-tumor effects in preclinical models. The presence of the "inflamed" gene signature was associated with a type I IFN transcriptional profile, and murine experimental models have confirmed a critical role for type I IFN signaling in promoting adaptive immunity."

So,In the first subset, tumors had a suppresive nature that may be over riddden by Anti-CTLA-4 (Yervoy) and or Anti-PD-1 Therapy

The second subset was missing the "danger signal" inflammatory cytokines and chemoattractants most likely due to STAT3 signaling from the Tumor.

Stimulation of Toll-like receptor 4 (TLR-4) activates macrophages and results in the release of TNF-alpha. It is hypothesized that melanoma inhibits macrophage activation by suppressing TLR-4 signaling.

Cytokines are small proteins which allow cells of the immune system to communicate with one another via cytokine receptors expressed at the cell surface.
Activated macrophages defend against tumors by secreting cytokines to recruit secondary immune cells, presenting antigen to T cells, and by direct tumor cytotoxicity. Peritoneal macrophages harvested from melanoma-bearing mice are less cytotoxic to melanoma cells, and produce less superoxide, nitric oxide, and tumor necrosis factor-alpha (TNF-alpha) than those from nontumor-bearing mice. Similar impairment of macrophage activation occurs in vitro using media harvested from cultured melanoma cells.

Activated Macrophages secrete the following cytokines under different conditions:
IL-1,IL-12,IL-6, IFN-gamma/alpha/beta and TNF-alpha

IL-6

Interleukin 6 is a pro-inflammatory cytokine and is produced in response to infection and tissue injury. IL-6 exerts its effects on multiple cell types and can act systemically.

IL-6 stimulates liver secretion of acute phase proteins
IL-6 stimulates B-lymphocytes to produce antibodies
IL-6 in concert with IL-1b causes T-cell activation
IL-6 induces STAT 3 Signaling
IL-6 Plus TGF-b induces the Th17 cell phenotype

IL-1 beta

Interleukin-1b is a pro-inflammatory cytokine which is secreted by macrophages activated by a number of stimuli including TNF-alpha, bacterial endotoxin and IL-1b itself.
IL-1b exerts its effects on many different cell types locally at the site of production and systemically (at a distance).

IL-12

Interleukin-12 is a heterodimer consisting of a p35 and a p40 subunit. Both subunits are required for receptor binding and biological activity.
IL-12 stimulates growth of activated Natural Killer (NK) cells, CD8+ and CD4+ T- cells.
IL-12 increases NK and T-cell g-IFN production which shifts T-cell differentiation towards a Th1-type response.
IL-12 increases NK production of TNF-alpha which can act synergistically with IFN-gamma.
IL-12 suppresses IL-4 induced IgE production.

TNF-alpha

Tumor Necrosis Factor alpha is made by many other cells as well as macrophages, which are major sources, especially after priming by Interferon gamma.
TNF-alpha initiates a cascade of cytokines which mediate an inflammatory response. TNF-alpha effects are mediated through two types of receptor, a 75kDa TNFR-a receptor and a 55kDa TNFR-b receptor.
TNF-alpha regulates the expression of many genes in many cell types important for the host response to infection.

IFN-gamma/beta

Macrophages, and many other cells produce these Type I interferons which act as immunomodulatory, as well as antiviral cytokines. Distinct receptor from interferon gamma, mediates overlapping or competing effects on macrophages. Cellular signalling pathways involve Jak/Stats, and other pathways.

So, if Melanoma suppresses Macrophage Activation, then the tumor microenviroment is missing IL-6, IL-1b and other cytokines.

If you look at the above micrographs, you will see that the two patients that had relapsed (10710 and 10737) Had IL-1b and IL-6 missing. The macrophages were not activated!!!! The "Danger Signal" known as inflammation was missing!

The missing combination of IL-1 and IL-6 meant there is no T-cell activation. And no induction of the Th17 phenotype. It is now becoming a lot more clearer based on Dr. Gajewski's findings.

Now might be the time for a critical re-evaluation of our overall approaches to targeting STAT3 and for developing new models for disrupting the protein in order to accomplish the goal of delivering clinically useful direct STAT3 inhibitors as novel anticancer agents in a timely manner.

“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”

~Charles Darwin~
Take Care,
Jimmy B

MedImmune Inks Deal for Pfizer's Anticancer mAb Therapeutic..Melanoma .Jim Breitfeller

2011-10-03T18:00:00.003-04:00

MedImmune inked an in-license agreement with Pfizer for tremelimumab, a mAb therapeutic for various types of cancer. Pfizer presented final toxicity results of a Phase I dose-escalation trial of tremelimumab in combination with gemcitabine in chemotherapy-naive patients with metastatic pancreatic cancer.

Under terms of the deal MedImmune will assume global development rights to tremelimumab. Pfizer retains rights to use the drug compound with specified types of combination therapies.

Pfizer previously signed over developments rights covering tremelimumab in melanoma to Debiopharm after the mAb failed in a Phase III melanoma trial. The interim analysis found that it would not offer any benefit over standard chemotherapy. Thus in April 2008, Pfizer was forced to halt the trial.

A full evaluation of the data revealed a biomarker that predicted patients who were more likely to respond, according to Pfizer. Debiopharm will be responsible for conducting a new Phase III study that leverages this marker to select patients with unresectable, stage IV melanoma. At the time of inking the deal with Debiopharm, Pfizer said it would retain all commercial rights.

Tremelimumab is a fully human mAb that binds to the protein CTLA-4, expressed on the surface of activated T lymphocytes. "Adding another immunotherapeutic approach to our oncology pipeline, one which may employ the immune system itself to fight cancer, exemplifies our continued commitment to embracing this new era of cancer care," says Bahija Jallal, Ph.D., MedImmune's evp, R&D.

MedImmune has seven clinical-stage mAb programs for cancer treatment. Phase I candidates bind to CEA and CD3, CD22, IGF, CD19, and Ang2. The Phase II candidate targets PDGFRα and is being tested in lung cancer and glioblastoma. The company believes that the platelet-derived growth factor receptor alpha (PDGFRα) pathway, with its potential role in regulating transformation as well as tumor microenvironment, progression, and metastasis, may be an important cancer target.

MEDI-575 is a fully human mAb to PDGFRα being tested in lung cancer. It has been shown to inhibit signaling from PDGFRα on cancer cells and supportive stroma. However, MEDI-575 reportedly does not inhibit PDGFRβ, the inhibition of which has been associated with significant clinical toxicities including extravascular fluid accumulation.

MEDI-575 is a fully human mAb to PDGFRα being evaluated as a treatment for glioblastoma multiforme. MEDI-575 has been shown to inhibit signaling from PDGFRα on cancer cells and supportive stroma but not PDGFRβ, MedImmune says

Bristol Myer Squibb will now be looking in the rearview mirror and seeing MedImmune in it. Down the road we may see the price of these anti-CTLA-4 antibodies go down.

Also MedImmune has an US Patent Application 20100028330 - METHODS OF UPMODULATING ADAPTIVE IMMUNE RESPONSE USING ANTI-PD1 ANTIBODIES.

This is becomming Very Intersesting!!!

A race for the CURE!!!!!

It is good to see some Competition.

“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”

~Charles Darwin~

Take Care,

Jimmy B

The Anti-PD-1 Therapy Race for Approval by the FDA is On..Melanoma ..Jim Breitfeller

2011-09-28T10:03:00.009-04:00

When it rains, it pours!!!! Melanoma patients over the last twenty years have not seen any progress in the fight to cure Melanoma. That has all changed in 2011 when the FDA approved Yervoy (Ipi..Ipilimumab), an anti-CTLA-4 monoclonal antibody and Zelboraf (vemurafenib). Well, this all going to change Melanoma from a cancer to a chronic disease that may be stabilized or even cured. The new Kid on the block( PD-1) is another Surface molecule that is unregulated when the T-cells are activated. This molecule is time dependent , which means that over time it migrates to the surface. Base on the research today, PD-1 molecule causes global inhibition to activated T-cells and down regulates the IL-2 expression by the PI3K/Akt pathway. It also inhibits the ICOS molecule that is an important co-stimulator for the T-cells.

So with stakes high to be the first to market, Bristol Myer Squibb, a little known company, Amplimmune, co-sponsored by GlaxoSmithKline and Curetech, a subsidiary of Teva Pharma of Israel are in the race of their lives. Winner takes all. And to throw Icing on the cake, the blockage of both inhibitors (PD-1 and CTLA-4) have shown remarkable ability to eradicate Melanoma tumors in mice.

Bristol Myer Squibb seems to be leading this race with a clinical trials recruiting at Sloan Kettering in New York and Yale in Connecticut.

The study is “Dose-escalation Study of Combination BMS-936558 (MDX-1106) and Ipilimumab in Subjects With Unresectable Stage III or Stage IV Malignant Melanoma”
Trial: NCT01024231

So with this in mind, if was seeking to try a clinical trial at this time, I would seek out the combination first, then PD-1 and if all else fails, Anti-CTLA-4 therapy followed by IL-2.

I see a Stabilization/Cure on the horizon for this disease and others based on these immunotherapies.

“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”
~Charles Darwin~
Take Care,
Jimmy B

Why Is Interleukin-2 so important for mounting an immune response?.Melanoma..Jim Breitfeller

2011-09-26T17:13:00.009-04:00

The T-cell-specific cell-surface receptors CD28, CTLA-4, ICOS and PD-1 are important regulators of the immune system. CD28 potently enhances those T-cell functions that are essential for an effective antigen-specific immune response, and the homologous CTLA-4 counterbalances the CD28-mediated signals and thus prevents an otherwise fatal overstimulation of the lymphoid system. PD-1 engagement can prevent ICOS but not CD28 costimulation. The inability of ICOS costimulation to override PD-1 inhibition is directly related to the low IL-2 levels it induces upon its engagement. ICOS Costimulation requires IL-2 and can be prevented by CTLA-4, PD-1 engagement. With the CD3/CD28 blocked downstream at the P13K and the Akt pathways, the T-cell is activated but the proliferation and survival of T-cells/immune response is terminated.

A picture is worth a thousand words.

Based on the above model, Downstream of the CD3/CD28 signaling the co-inhibitors down modulate the P13/Akt signaling. Signaling via CD28 is required for optimum IL-2 production, cell cycle progression, and survival. CD28 is constitutively expressed on naive CD4+ T cells is slightly upregulated after T cell activation.

The CTLA-4 and the PD-1 expression increase over time in Melanoma patients. This is why it is so very hard to eradicate Melanoma in the late stage IV.

To counteract the inhibition, one can use Antibodies to block the suppressive signaling coming from the CTLA-4 and PD-1. This is where Yervoy (Anti-CTLA-4) and Anti-PD-1 come into play. So if you can do a therapy with a systematic approach, you may be able to beat Melanoma.
It is now known, that IL-2 can down regulate PD-1 receptor so you might not need to do Anti-PD-1 therapy. Or you might do anti-PD-1 instead of IL-2 therapy to cut down the harsh effects of the IL-2 therapy. It is now known that the T-cell activation/immune response needs IL-2 to produce a robust immune response.

“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”

~Charles Darwin~

Take Care,

Jimmy B

Ultimate fate of cellular immune responses is determined by the balance between positive & negative signals delivered by T-cells..Melanoma ..Jim Breit

2011-09-23T21:47:00.013-04:00

ICOS Expression,To secrete and what to secrete is the question.

My research has taken me to the costimulators and coinhibitors of the T-cell activation. The Delicate balance between the costimulators and coinhibitors render the right immune response at the right time. One of these costimulators is the ICOS. But if there is to much ICOS, then there is a down regulation of the the immune response by the secetion of IL-10 into the tumor's microenviroment.

The level of ICOS surface expression regulates the magnitude of the in vivo Th1/Th2 ratio, perhaps by influencing Th2 differentiation. This regulation plays a major role in the differentiation of the T-cells.

The linkage between low ICOS expression and “early” cytokines, and between intermediate/high ICOS expression and “late” cytokines is intriguing and could mean that ICOS is gradually up-regulated in the course of progressing T cell differentiation.

ICOS-low-cells were found to be loosely associated with the early cytokines interleukin (IL)-2, IL-3, IL-6, and interferon (IFN)-gamma.

ICOS-medium cells, the large majority of ICOS_ T cells in vivo, were very tightly associated with the synthesis of the T-helper type 2 (Th2) cytokines IL-4, IL-5, and IL-13, and these cells exhibited potent inflammatoryeffects in vivo.

In contrast, ICOS-highT cells were highly and selectively linked to the antiinflammatory cytokine IL-10.

The strength of the effector response of Th cells is regulated by the control of ICOS expression.

Overall, this data seem to indicate that ICOS cell surface density serves as a regulatory mechanism for the release of cytokines with different immunological properties.

We want the low expression of ICOS which seems to differeniate the niave T-cells towards the TH1 T-cell phenotype. We can accomplish that with Yervoy (Anti-CTLA-4). STAT5 signaling is found in both the Th2 and Treg pathway.It just so happens Yervoy causes the phosphorylation of STAT5 to decreased significantly with increasing concentrations . Yervoy skews the T-cell differentiation towards the Th1/Th17 phenotype which we want.

Another coinhibitor which surpresses the immune resonse is (PD-1) Program Death 1.

Blockade of PD-1 by monoclonal antibodies specific to its ligands (PD-L1 and PD-L2) results in significant enhancement of proliferation and cytokine (gamma interferon [IFN-gamma] and interleukin-2 [IL-2]) secretion by tumor-specific CTLs. PD-1 blockade also resulted in down-regulation of intracellular FoxP3 expression by Tregs.

So by do a combinatorial therapy with Yervoy and PD-1 antibodies, It would most likely have a synergistic immune response.

This why on 9-20-2011, Bristol Myer Squibb expanded it's deal with Japan's Ono Pharmaceutical Co. Ltd. BMS now knows that they have an monopoly on T-cell activation and can be applied to many other cancers besides Melanoma. They are collecting the "String of Pearls". It would not surprise me they will go after the rest of the costimulators and coinhibitors on the T-cells. Only time will tell.

My hope is that Bristol Meyer Squibb uses it for the cure of cancer one day and not just monetary gains.

“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”
~Charles Darwin~
Take Care,
Jimmy B

How does Ipilimumab (Yervoy) work? Melanoma..Jim Breitfeller

2011-08-26T14:27:00.008-04:00

Ipilimumab is anti-CTLA-4 monoclonal antibody.

Ipilimumab C6742H9972N1732O2004S40
immunoglobul has a calculated molecular formula of C6472H9972N1732O2004S40 and a molecular weight of 145.4 kDa.in G1, anti-(human CTLA-4 (antigen)) (human gamma1-chain), disulfide with human kappa-chain, dimer [CAS] immunoglobulin G1, anti-(human CTLA-4 (antigen)) (human g1-chain), disulfide with human k-chain, dimer [CAS]

Half Life = 15 days

Tremelimumab (from Pfizer) is an IgG2
Tremelimumab is a fully human cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) IgG2 monoclonal antibody, presumably manufactured using transformed mammalian cells. Tremelimumab is a dimer (composed of two chains) linked by a disulfide/sulfhydryl bond. Tremelimumab has a calculated molecular formula of C6500H9974N1726O2026S52 and a molecular weight of ~150 kDa

Half life= 21 days

In T-cell activation, the receptor, CTLA-4 is upregulated on about day 3.

The CTLA-4 complex can suppress the immune response.

CTLA-4 that interferes with Dendritic cell (DC) costimulation via reduced CD80/CD86, (B7-1-2) expression and CD25 (IL-2 receptor) to allow for Treg survival, activation, and effective competition for limited IL-2 during infection.

Ipilimumab (Yervoy) works by blocking the CTLA-4/ B7-1/2 complex, which allows the costimulation of the CD28// B7-1/2 complex to take place. This takes the brakes off the immune response allow the response to go unchecked.

Another thing Yervoy does is that it decreases the signaling of STAT5 with increasing concentrations. That is why the best overall concentration is 10mg/Kg.

Phosphorylation of STAT5 decreased significantly with increasing concentrations of tremelimumab/Ipilimumab in monocytes from five healthy donors and from three patients with melanoma. Overall, these data demonstrate that monocytes express mostly intracellular CTLA4 and that CTLA4 is biologically active in this cell subset since exposure to tremelimumab/ipilimumab induces changes in intracellular signaling molecules.
By decreasing the signaling of STAT5 during Cell differentiation, TH17 and TH1 cells are mostly produced.

“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”
~Charles Darwin~
Take Care,
Jimmy B

FDA approval of Roche melanoma drug (Vemurafenib) may come early

2011-08-09T12:30:00.004-04:00

Reuters) - Regulators are moving quickly with Roche's application for targeted melanoma drug vemurafenib, which could receive approval as early as this week, according to a source familiar with the situation.

Vemurafenib, whose brand name is Zelboraf

Source: FDA approval of Roche melanoma drug may come early

Your tumors must be BRAFV600E positive

“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”

~Charles Darwin~

Take Care,

Jimmy B

Melanoma International Foundation Exposed!!!! Melanoma ..Jim Breitfeller

2011-07-17T11:24:00.007-04:00

In the last couple of days I have been comunicating with a caregiver on the subject of Help! Interleukin-2 or Yervoy?? (lauram)Posted: 1:38:56 pm on 7/15/2011

As I went into my posts I linked some papers that I wrote on the subject matter. It was based on years of research and I thought it had some added value to the subject.
Posted:

"Based on my interpretation of the science, I would do Ipilimumab (Yervoy) first. Make sure you have your ALC (Absolute Lymphocyte count) tested before the trial. If it doubles by week 7, you are most likeely a responder. If not, do the HD-IL-2 regime. Here is a paper that may help you understand the science behind the treatment."

Well, I was in great disbelief that Catherine Poole, the President and Founder of the Melanoma International Foundation had deleted my link and said

Re: Help! Interleukin-2 or Yervoy?? (Catherine Poole)
Posted: 12:24:21 pm on 7/16/2011 Modified: 12:27:43 pm on 7/16/2011

"Jimmy,

I don't think this is based on "the science" but more your opinion on the science. It just hasn't been proved in enough of the population to warrant the recommendation. We must be careful in these assumptions we make. So please do not suggest that here to patients without ample evidence in large segment of the population. We had to edit out your link since it appeared to be a virus within it."

I contunued to post links to clinical data that backed up the science.

Re: Help! Interleukin-2 or Yervoy?? (jimmy_b)
Posted: 8:57:41 pm on 7/16/2011 Modified: Never

Catherine, if you read my intial post: I said"

Based on the science, I would do Ipilimumab (Yervoy) first. Make sure you have your ALC (Absolute Lymphocyte count) tested before the trial. If it doubles by week 7, you are most likeely a responder. If not, do the HD-IL-2 regime. Here is a paper that may help you understand the science behind the treatment."

I am saying the what you are. Do Yervoy first. If you fail, then try HD IL-2. A response from IL-2 can be durable and long lasting (Over 10 Years in some cases)

Patient information:Melanoma treatment; advanced or metastatic melanoma

Author Jeffrey A Sosman, MD

http://www.uptodate.com/contents/patient-information-melanoma-treatment-advanced-or-metastatic-melanoma

MELANOMA TREATMENT

Treatment of metastatic melanoma focuses on:

Shrinking or getting rid of metastases

Preventing the disease from spreading

Keeping you comfortable

In most cases, it is not possible to completely eliminate or cure the cancer. Depending upon where and how big the metastases are, treatment may involve drug treatments, surgery, or radiation therapy.

Drug treatments — There are three main categories of drug treatments:

Immunotherapy – drugs that work with your immune system to stop or slow the growth of cancer cells

Chemotherapy – drugs that stop or slow the growth of cancer cells by interfering with their ability to divide or reproduce themselves

Molecularly targeted therapy- drugs that act to inhibit specific pathways or molecules important to the cancer cells

These drug treatments may be given alone or in combination. Most of these treatments must be given into a vein (intravenously) or injected under the skin, although a few can be given in pill form. Each medication is given over a period of time, sometimes up to several months, depending upon how you respond.

Immunotherapy — Because immunotherapy works differently than chemotherapy, it has different side effects.

Interleukin-2 (IL-2) — IL-2 is a form of immunotherapy that has been found to help some people with metastatic melanoma when given in high doses. In some people treated with high dose IL-2, the benefit can be long-lasting [1-3].

However, high dose IL-2 can cause serious and toxic side effects and it is generally reserved for people who are otherwise healthy (with good heart and lung function).

IL-2 is usually given into a vein three times per day for five days twice per month. Treatment is usually completed while you are in the hospital.

Potential side effects of IL-2 — Potential side effects of high dose IL-2 include low blood pressure, irregular heart rhythms, accumulation of fluid in the lungs, fever, and rarely death.

Ipilimumab — Ipilimumab is a drug that stimulates the body’s immune system to react against the melanoma. This is given once every three weeks for a total of four doses. Treatment with ipilimumab may decrease the extent of your melanoma and help you live longer. But ipilimumab can also cause the body to develop an immune reaction against its own tissues. This can result in a wide range of side effects that may be severe or life threatening. The most important of these include colitis (causing diarrhea, bleeding, or more serious complications), hepatitis, rash or inflammation of the skin, and inflammation of endocrine organs (pituitary, thyroid, or adrenal). If this occurs, you might have to stop the ipilimumab and receive additional treatment for the complications.

If you take this drug, it is important to tell your doctor about any side effects you experience, even mild ones. This will help avoid the more serious complications.

MELANOMA SURVIVAL

Significant progress has been made in the treatment of metastatic melanoma over the past decade. Two drugs that stimulate the immune system, high dose interleukin-2 (IL-2) and ipilimumab, are more effective for controlling metastatic melanoma and allowing some people to live longer. However, both of these forms of immunotherapy can be associated with severe side effects.

In deciding what treatment is right for you, you and your family must consider the risks and benefits of each option according to your values and preferences."

warm regards

Jimmy B
Melanoma Missionary

Advances in Immunotherapy for the Treatment of Metastatic Melanoma

For your Information:

http://www.asco.org/ascov2/Home/Education%20&%20Training/Educational%20Book/PDF%20Files/2011/zds00111000363.PDF

"THE FIRST randomized clinical trial demonstrating an effect on patient survival for the treatment of metastatic melanoma has been recently reported using the immune-stimulating antibody ipilimumab.

This is an important advance in this disease as well as a proof of concept of the ability of immunotherapy to affect the natural course of advanced melanoma. However, the objective tumor response rates are low with CTLA4-blocking antibodies. Response rates up to 50% to 70% have been achieved with an optimized combination of ex vivo, clonally expanded, tumor-infiltrating lymphocytes (TILs) administered after lymphodepleting chemotherapy and followed by high-dose IL-2 administration."

"This provides further evidence of the potential of immunotherapy for the treatment of melanoma."

Dr. Antonio Ribas 2011

My Therory, is that instead of clonally expanding the (TILs) tumor-infiltrating lymphocytes ex vivo, and not depleting the Tregs, WE are doing it all in vivo (Inside the Body). The reason we skip the Lymphodepleting is that the CD4-T-cell in need to secrete just the right amount of IL-2 to activate the and prime the CD-8 T-cells. The High dose IL-2 is there to muture the CD8- T-cells into Cytotoxic T lymphocytes (CTLs).

I know there are skeptics out there, but we need to read the research papers that are cutting edge to make any progress. Why is Dr. Steven Rosenberg using IL-2 in his ACT therapy?

You need to think outside the box and not reject things that you don't understand.
best regards

Again Catherine poole responded:

Again, Jimmy, we don't believe the science until it is proven in many individuals. Hundreds of patients should show these results before it is proven fact and enough to base an opinion about. Rosenberg has been using IL2 for 20 years or more, it is his drug of choice. Why? I'm not certain, but I've not been impressed by the results of research at NCI in melanoma. So I imagine there is funding from the industry for this particular drug to be used. And they need funding desperately for melanoma at NCI, it is not a priority. I would just suggest that our recommendations be based on large studies here and so far Yervoy has more promise than IL2 and is far less debilitating..

Catherine M. Poole, President/Founder

Melanoma International Foundation

Again I responded with :

Re: Help! Interleukin-2 or Yervoy?? (jimmy_b)
Posted: 9:58:59 pm on 7/16/2011 Modified: Never

Ipilimumab in Combination with IL-2

Author: Jeffrey Weber, M.D., Ph.D., H. Lee Moffitt Cancer Center

July of 2008

Thirty-six patients with stage IV metastatic melanoma were treated with ipilimumab at doses in the range of 0.1–3mg/kg every 3 weeks combined with IL-2 at 720,000 IU/kg every 8 hours to a maximum of 15 doses [20]. There was an ORR of 22%, with three patients having a CR and five patients having a PR. Five of the responses occurred among the 24 patients treated with ipilimumab at 3 mg/kg, and one each occurred in those treated with 0.3, 1, and 2 mg/kg. Six of the eight responders had ongoing responses at follow-up of 11–19 months. The 22% ORR reflects an additive rather than a synergistic effect for these two agents, although durable responses were demonstrated.

Based on the initial experience with ipilimumab in combination with chemotherapy or IL-2, additive effects have been seen, as opposed to synergy. However, the results from these trials suggest that combination therapy with ipilimumab may play an important role in the treatment of metastatic melanoma; larger trials are required, including an ongoing phase III trial of ipilimumab plus dacarbazine compared with dacarbazine alone in frontline therapy, before further conclusions can be drawn.

http://theoncologist.alphamedpress.org/content/13/suppl_4/16.full

Jimmy B
Melanoma Missionary

Re: Help! Interleukin-2 or Yervoy?? (jimmy_b)
Posted: 10:35:56 pm on 7/16/2011

Cytotoxic T lymphocyte-associated antigen 4 blockade with ipilimumab: Long-term follow-up of 179 patients with metastatic melanoma 2010 ASCO Annual Meeting

Abstract No:8544

Citation:
J Clin Oncol 28:15s, 2010 (suppl; abstr 8544)

Author(s):

P. A. Prieto, J. C. Yang, R. M. Sherry, M. S. Hughes, U. S. Kammula, D. E. White, C. L. Levy, S. A. Rosenberg, G. Q. Phan; Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD; National Cancer Institute, National Institutes of Health, Bethesda, MD; National Cancer Institute, Bethesda, MD; Surgery Branch, National Cancer Institute, Bethesda, MD

Abstract:

Background: We have previously shown objective clinical responses in patients with metastatic melanoma treated with CTLA-4 blockade using ipilimumab. We have treated 179 patients in 3 separate clinical trials and now have long-term follow-up to evaluate the durability and unique features of this immunotherapy. Methods: A total of 179 patients with metastatic melanoma were treated in 3 trials: In Protocol 1, 56 patients received ipilimumab with gp100 peptide vaccines. In Protocol 2, 36 patients received ipilimumab with high-dose interleukin-2 (IL-2). In Protocol 3, 87 patients received intra-patient dose escalation of ipilimumab and were randomized to receive gp100 peptides. We have updated and analyzed the follow-up and survival data for these trials. Results: With median follow-up for Protocol 1, 2, and 3 being 80, 71, and 60 months, median survival was 15, 16, and 13 months, respectively. Objective tumor regression was 12% for Protocol 1, 25% for Protocol 2, and 21% for Protocol 3. Patients in Protocol 2 had a 17% complete response rate (6 patients: 77+, 74+, 72+, 71+, 71+, and 69+ months), as compared to 7% in Protocol 1 (4 patients: 82+, 81+, 79+, and 66+ months) and 8% in Protocol 3 (5 patients: 64+, 63+, 62+, 60+, and 55+ months); all complete responses are ongoing. Many patients who eventually became complete responders had continual tumor shrinkage after stopping therapy. Conclusions: CTLA-4 blockade with ipilimumab can achieve durable objective tumor regression in patients with metastatic melanoma. The combination of ipilimumab and IL-2 appears to have an increased complete response rate, although this needs to be tested in a prospective randomized trial. This report represents the largest single-institution experience with the longest follow-up for this agent; our results support its role as a viable treatment option for patients with metastatic melanoma.

Catherine My Theory does have Merit. It is the Science backup with some clinical Data.

Lets Think OUTSIDE THE BOX!!!!

best regards

Jimmy B
Melanoma Missionary

Re: Help! Interleukin-2 or Yervoy?? (Catherine Poole)
Posted: 7:10:37 am on 7/17/2011 Modified: 7:15:36 am on 7/17/2011

This just isn't the place for you to post all of this. Just give the citations. As I mentioned in the other response to your post, you are not a peer reviewed credentialled medical researcher. We always think outside the box here but we also keep in mind the validity of research and whether large numbers of people benefitted. We also talk in terms that people can understand easily. You are a missionary by your self description, bent on a mission and we are navigators exploring all options.

Catherine M. Poole, President/Founder

Melanoma International Foundation

The MIF Website and Forums are designed for educational purposes only and are not engaged in rendering medical advice or professional services. The information provided through this Website should not be used for diagnosing or treating a health problem or a disease. It is not a substitute for professional care. If you have or suspect you may have a health problem, you should consult your health care provider.

Re: Help! Interleukin-2 or Yervoy?? (Catherine Poole)
Posted: 7:12:02 am on 7/17/2011 Modified: Never

This just isn't the place for you to post all of this. Just give the citations. As I mentioned in the other response to your post, you are not a peer reviewed medical researcher.

Catherine M. Poole, President/Founder

Melanoma International Foundation

The MIF Website and Forums are designed for educational purposes only and are not engaged in rendering medical advice or professional services. The information provided through this Website should not be used for diagnosing or treating a health problem or a disease. It is not a substitute for professional care. If you have or suspect you may have a health problem, you should consult your health care provider.

Re: Help! Interleukin-2 or Yervoy?? (jimmy_b)
Posted: 8:21:51 am on 7/17/2011 Modified: Never

Catherine, What credentials do you have may I ask. How many patents do you have. I rest my case.

You are blinded by your own lack of understanding.

Jimmy B

Re: Help! Interleukin-2 or Yervoy?? (Catherine Poole)
Posted: 7:10:37 am on 7/17/2011 Modified: 10:53:34 am on 7/17/2011

This just isn't the place for you to post all of this and we don't like our forum to have the negativity that you exhibit. Just give the citations as you are taking space away from others. As I mentioned in the other response to your post, you are not a peer reviewed credentialed medical researcher. I have never claimed to be either. I rely on the opinion of medical experts who are credentialed and peer reviewed in their work in melanoma research from the outstanding cancer centers who specialize in melanoma. We always think outside the box here but we also keep in mind the validity of research and whether large numbers of people benefitted. I know you are promoting what worked for you and then backing it with research you have found that could be interpreted in a different light. We also talk in terms that people can understand easily. You are a missionary by your self description, bent on specific therapy mission and we are navigators exploring all options. You have your own website for that purpose and we'd appreciate you keeping your lengthy opinions there.

Catherine M. Poole, President/Founder

Melanoma International Foundation

This forum is moderated by specialists in melanoma, primarily by volunteer dermatologists and oncologists on a weekly basis. In addition, Catherine Poole, President and Founder of the Melanoma International Foundation, a melanoma survivor, and patient navigator for 20 years and co-author with DuPont Guerry, MD a melanoma expert, of Melanoma, Prevention, Detection and Treatment, (Yale University Press: 2005) monitors this site many times daily. Information on

Re: Help! Interleukin-2 or Yervoy?? (jimmy_b)Posted: 11:33:12 am on 7/17/2011
Laura,

Re: Help! Interleukin-2 or Yervoy?? (jimmy_b)
Posted: 11:33:12 am on 7/17/2011 Modified: Never

Laura,

Thanks, as you can see, Catherine Poole is pushing her own agenda and has delete my entries.

What happen to the Freedom of Speech act?

This forum is NOT moderated by specialists in melanoma, primarily by volunteer dermatologists and oncologists on a weekly basis. This is very Sad.

Jimmy B
Melanoma Missionary

If you go to Melanoma International Foundation for advice, You may not be getting the whole picture.

I was not pushing my theory, I was giving my opinion. As for Catherine M. Poole,
who is sending out The Negativity.

"We don't like our forum to have the negativity that you exhibit."
~Catherine M. Poole_

You be the judge

I don't delete links and entries or comments on my web blog. Everyone is entitled to their opinoin.

“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”

~Charles Darwin~
Take Care,
Jimmy B

After Activation With Yervoy, IL-2 Produced by Activated CD4+ T Cells Helps CD8+ T-Cell Activation.Melanoma..Jim Breitfeller

2011-07-14T09:31:00.004-04:00

YERVOY™ (Ipilimumab) Approved For The Treatment Of Previously-Treated Advanced Melanoma In The EU
Posted 6 minutes ago
Article Date: 14 Jul 2011 - 4:00 PDT

Bristol-Myers Squibb today announced that the European Commission has approved YERVOY™ (ipilimumab) for the treatment of adult patients with previously-treated advanced melanoma.

After Activation With Yervoy, IL-2 Produced by Activated CD4+ T Cells Helps CD8+ T-Cell Activation.

IL-2 Is Critical to CD8+ T Cell Activation at Early Time Points during Priming.

The Action of IL-2 on CD8+ T Cells Is through IL-2 Receptor
IL-2 signals to naïve CD8+ T cells through IL2 Receptor

It is hypothesized that IL-2 may help CD8+ T cell activation through enhancing the signal that drives proliferation.

IL-2 Signaling during Priming Helps CD8+ T Cells Acquiring Effector Functions,

Generation of Potent CD8+ T Cell Anti-Tumor Effector Function Depends upon IL-2 Help.

IL-2 signal at priming drove better anti-tumor CTL function in vivo.

This is why Combinatorial Therapy is a Must to CURE Melanoma

Yervoy (Ipilimumab) + IL-2 = Melanoma CURE!!!!

You must get the tumors's microenviroment in the right configuration for it to work.

“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”

~Charles Darwin~
Take Care,

Jimmy B

ASCO Review with Dr. John Kirkwood on Melanoma Therapies..jim Breitfeller

2011-06-28T16:14:00.004-04:00

The full Audio of the Dr. Kirkwood interview at ASCO 2011

Please if you get a chance, listen to the full interview of Dr. John Kirkwood on the lastest therapies for Melanoma. It might help save your life or loveone's life.

Get a cup of coffee and a pad and pencil.

Enjoy

“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”
~Charles Darwin~

Take Care,
Jimmy B

Yervoy.. The Magic Bullet!!..Melanoma..Jim Breitfeller

2011-06-24T09:20:00.003-04:00

Hi everyone

I´ve been reading posts at this Bulletin Board for almost a year now. Some posts I have read with tears in my eyes, and some with joy. Here is our story (short version):

I am the husband to a 39 year old woman from Denmark in Europe.

In 2003 she had a mole removed from her thigh (Stage II). It contained melanoma-cells.

In 2007 melanoma had spread to a lymph-node in her groin (Stage III). Surgery was needed.

In 2008 melanoma relapsed in another lymph-node, surgery again.

In 2009 melanoma hit us hard (Stage IV). It had spread to her lungs, one met in each lung. The size of the mets was 25 mm and 16 mm respectively. Surgery was fortunately possible.

In October 2010 melanoma went back. This time there was multiples mets in each lung. About 5-6 mets in each lung. The biggest was 19 mm. It was unsurgeable, which was very hard to cope with.

In November she began Interferon/Interleukin-2 treatment. It was tough beyond imagination. She had all the known sideeffects, and she was so bad during hospitalization. The midway PET/CT scans in January revealed that she was a responder! Scans showed that all the mets had become inactive or necrotic. Some mets had even shrunk a little bit. We were delighted, and she continued with the third and fourth series of Interferon/IL-2.

February 15 we got the results of the next scan. We were optimistic because the midway scans was indeed promising. We were shocked when told that the melanoma had began to grow again. There was 2 active mets now. One big met, about 32 mm in diameter, in her right lung lightened up. In addiction there was a lot of fluid in the right lung membrane, and it probably contained melanoma-cells. All other mets was still inactive, except one, and our doctor feared that it would be only a matter of time, before the other mets would begin to grow again. We were devastated.

Our doctor suggested Ipilimumab, and my wife started March 11, on the same day Japan was shaken by the huge earthquake. I watched it on TV while she was receiving the first dose of ipilimumab (3 mg/kg dose). I remember wishing that the drug was the earthquake of our lives…

My wife have always been a positive and happy human being, no matter what challenges life would bring, she still truly believe that she could defeat this Melanoma Devil. She began consulting a Chinese doctor and received acupuncture twice a week. Beside this she trained 4-5 times a week, fitness and running. In these situations we talked about preparing your body to fight the cancer, with a "little" help from our friend, ipilimumab…

She received 4 doses every third week and got a CT scan in June.

Three days ago on June 21 we arrived to the hospital to talk with our doctor about the results of the CT scan. The time from the scans being done and to get the results is awful with a lot of anxiety, you guys all know… The scan showed that the 32 mm met in the right lung was completely GONE!!!!! The fluid was gone too, and the x-ray showed a nice healthy looking right lung. We were stunned. I hugged my wife with a lot of tears in my eyes. Our doctor was very delighted too. Ipilimumab had worked much better than expected. We had hoped for stabilization, maybe shrinkage, if we were lucky. But this???? Unbelievable. Some other small mets was still there but hasn´t grown in size in half a year, and our doctor said it very well could be necrotic tissue.

This is where we stand now. We´re thrilled and delighted and so so happy. We have now dared to plan for more than a month :-)

So this story is to all you Warriors out there, keep on fighting with believe and trust in your hearts. The path is very tough but the battle can be won, sooner or later. We´ll keep fighting this Devil.

Kind regards

willtolive

========================================================================

Did High Dose Interferon Alpha set the stage for the perfect Orchestration of an Immune Response?

As I continue my search for the Holy Grail, I need to keep grounding myself to what really took place in the Melanoma treatment. I can not keep wondering if Interferon therapy had played a part in our successful treatment.

Both Vicky and I did some IFN therapy first.

Vicky’s Treatment timeline:

1) Diagnosis 5/10/06
2) Excision and sentinel node biopsy 5/16/06. SN positive, MM 3.3 mm, amelanotic, ulcerated (I did just read that the ulcerated variant does seem to do well with high-dose interferon in terms of prolonging survival)
3) Elective radical lymph node dissection, right groin, 5/30/06 2 more positive lymph nodes
4) High-dose iv interferon all of July 2006, followed by subcutaneous interferon MWF for 2 months.
5) Enroll in anti-CTLA-4 study as adjuvant therapy for stage 3 MM with Dr. Jeffrey Weber at USC. First dose of intravenous infusion of anti-CTLA-4, dose of 10 mg/kg early Nov 2006, second dose was Jan. 9, 2007.
6) Chest CT, routine, for the study, was positive for bilateral pulmonary nodules on 1/18/07
7) Lung biopsy positive for MM on 2/03/07
8) First course of high-dose IL-2 was March 2007
9) 60% reduction in tumor burden on April 23 CT scans
10) Second course of IL-2 in June 2007 ( I believe I got 14 of 14 doses during the 3rd cycle or week 1 of the second course.
11) Complete response seen on CT 8/01/07
12) Took an elective 5th cycle of IL-2 in early September of 2007- got quite sick and stopped. I think I got around 9 doses that last time.

Did High Dose Interferon Alpha set the stage for the perfect Orchestration of an Immune Response?

“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”

~Charles Darwin~

Take Care,

Jimmy B

2011 ASCO Annual Meeting Highlights on Melanoma and Neuroblastoma, with Lynn Schuchter, MD ..jim breitfeller

2011-06-14T15:31:00.004-04:00

2011 ASCO Annual Meeting Highlights on Melanoma and Neuroblastoma, with Lynn Schuchter, MD
June 5, 2011

2011 ASCO Annual Meeting Highlights on Melanoma and Neuroblastoma, with Lynn Schuchter, MD

“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”

~Charles Darwin~

Take Care,

Jimmy B

Bristol, Roche team up on melanoma study..Jim Breitfeller

2011-06-02T18:10:00.003-04:00

By Bill Berkrot and Lewis Krauskopf

NEW YORK | Thu Jun 2, 2011 1:30pm EDT

NEW YORK (Reuters) - Bristol-Myers Squibb and Roche Holding AG said on Thursday they would evaluate their respective cancer drugs as a potential combination therapy for metastatic melanoma.

The collaboration involves a Phase I/II study with Bristol's recently approved Yervoy and Roche's experimental drug, vemurafenib, to determine the safety and efficacy of the combination in treating the deadliest form of skin cancer.

The announcement comes as the American Society of Clinical Oncology meeting begins this weekend in Chicago, where emerging treatments for melanoma will be in the spotlight.

Among the most eagerly anticipated studies being presented at the ASCO meeting will be a Phase III trial intended to show that vemurafenib extended the lives of patients with advanced melanoma, and another study comparing Yervoy to chemotherapy in patients with the fatal disease.

Yervoy won U.S. approval in March for patients with inoperable or metastatic melanoma, making it the first new treatment option in many years for patients for whom there was little hope and virtually no effective medicines.

Roche and Japanese drugmaker Daiichi Sankyo Co recently submitted U.S. and European applications seeking approval for vemurafenib. The drug was developed by Roche's Genentech unit and Plexxikon, which was recently acquired by Daiichi.

Vemurafenib, a so-called BRAF inhibitor, is designed to selectively target and inhibit a mutated form of the BRAF protein found in about half of all cases of melanoma. The combination study with Yervoy will be in patients with BRAF-mutated metastatic melanoma, Roche said.

Roche is also developing a combination diagnostic to help identify those patients with the BRAF mutation who are likely to benefit from vemurafenib.

"We are entering a new era for melanoma, and are committed to studying exciting combinations with investigational medicines in our own pipeline," Roche Chief Medical Officer Hal Barron said in a statement.

If proven effective and approved the Yervoy-vemurafenib combination would be an extremely expensive treatment option that could meet with reimbursement resistance from government programs and health insurers.

Bristol priced a four-infusion course of Yervoy at about $120,000. Vemurafenib will likely also command premium pricing if it too demonstrates an ability to help patients live longer.

More than 70,000 people in the United States and 160,000 worldwide are diagnosed with melanoma each year, according to the American Cancer Society. The five-year survival rate for the aggressive cancer is just 15 percent.

Source:http://www.reuters.com/article/2011/06/02/us-bristol-roche-melanoma-idUSTRE75151W20110602

All I can say.... It is about Time!!!! Lets all work together for the common good.

“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”
~Charles Darwin~

Take Care,

Jimmy B

Ipilimumab and Beyond: New Therapies Imminent in Melanoma..Jim Breitfeller

2011-05-11T15:21:00.003-04:00

Ipilimumab and Beyond: New Therapies Imminent in Melanoma
By: SUSAN LONDON, Internal Medicine News Digital Network

05/11/11
LAS VEGAS – Melanoma has the fastest-rising incidence of any cancer, and exacts a terrible toll among individuals who are typically in the prime of their life. But historically, it has not been a major focus in oncology, in part because of its propensity to metastasize early and the very limited treatment options when it does.

This is changing – and not just because of the landmark clinical trial showing that ipilimumab (Yervoy) can prolong the lives of these patients, Dr. Steven O’Day, a lead investigator of that trial, told attendees at the annual Community Oncology Conference

Ipilimumab targets the immune system so that it can contain the cancer, rather than targeting the tumor to eradicate the disease, explains Dr. Steven O'Day.

Four new classes of therapies are improving outcomes in patients with metastatic melanoma, according to Dr. O’Day, director of the melanoma program at the Angeles Clinic and Research Institute in Santa Monica, Calif.

The rest can be viewed at Internal Medicine News

Remember:Ipilimumab and Beyond!!!!

You heard it first back in 2006 right here. It may not be a cure, but it is a durable response that can last for YEARS!!!

With combinatorial therapy, the response rate will improve greatly.

“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”
~Charles Darwin~

Take Care,
Jimmy B

Guess What, regulatory T cells (Tregs) control CD8+ T-cell..Melanoma ..Jim Breitfeller

2011-05-10T12:36:00.001-04:00

Guess What, regulatory T cells (Tregs) control CD8+ T-cell
effector differentiation by modulating IL-2 homeostasis.

Research done by Raymond J. Steptoe and colleages in a paper called
"CD4+CD25+ regulatory T cells control CD8+ T-cell effector differentiation by modulating IL-2 homeostasis"

"CD4+CD25+ regulatory T cells (Treg) play a crucial role in the regulation of immune responses. Although many mechanisms of Treg suppression in vitro have been described, the mechanisms by which Treg modulate CD8+ T cell differentiation and effector function in vivo are more poorly defined. It has been proposed, in many instances, that modulation of cytokine homeostasis could be an important mechanism by which Treg regulate adaptive immunity; however, direct experimental evidence is sparse. Here we demonstrate that CD4+CD25+ Treg, by critically regulating IL-2 homeostasis, modulate CD8+ T-cell effector differentiation. Expansion and effector differentiation of CD8+ T cells is promoted by autocrine IL-2 but, by competing for IL-2, Treg limit CD8+ effector differentiation. Furthermore, a regulatory loop exists between Treg and CD8+ effector T cells, where IL-2 produced during CD8+ T-cell effector differentiation promotes Treg expansion."

By controlling the Tregs with Ipi (Yervoy)and the timing of the addition of IL-2 therapy plus IL-12 if needed, one could generate the right immune response against the Melanoma Cancer.

My theory now has all the backing of reseachers and their papers.

We need to get the oncolgists to take a look at the combinatorial therapy

Of Yervoy (Ipi), IL-12 and IL-2. This could be the major breakthrough.

The Aha Moment!!!!!

“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”

~Charles Darwin~
Take Care,

Jimmy B

Researchers at UCLA's Jonsson Comprehensive Cancer Center Discover Way To Amp Up The Power Of Killer T Cells..Melanoma ..Jim Breitfeller

2011-05-10T11:47:00.004-04:00
Researchers at UCLA's Jonsson Comprehensive Cancer Center Discover Way To Amp Up The Power Of Killer T Cells

Article Date: 10 May 2011 - 1:00 PDT
Source: http://www.medicalnewstoday.com/articles/224693.php

Researchers with UCLA's Jonsson Comprehensive Cancer Center have discovered a way to amp up the power of killer T-cells, called CD8 cells, making them more functional for longer periods of time and boosting their ability to multiply and expand within the body to fight melanoma, a new study has found.

The study, done in mouse models of metastatic melanoma that had spread to the brain, has important clinical implications, as the method could boost the cancer-killing power of experimental immunotherapies being tested now in various cancers, including deadly glioblastoma and metastatic melanoma, both of which are very difficult to treat successfully.

Study senior author Dr. Robert Prins, an associate professor of neurosurgery and a Jonsson Cancer Center scientist, said the killer T cells also were better able to recognize and traffic to the cancer, which is crucial as the immune system often fails to identify malignant cells as invading enemies.

The study is published in the May issue of the peer-reviewed the Journal of Immunology.

The process Prins and his team used sought to mimic the way the T cells in the immune system recognize and fight viruses in the body, stimulating what is called the innate immune system. The innate immune system is comprised of cells that immediately defend the body from infection and frequently is not stimulated in the presence of cancer, Prins said. However, the innate immune cells can be tricked into thinking a virus is present by treating with compounds that activate Toll-like receptors (TLR).

Prins' group had previously demonstrated that TLR agonists, such as imiquimod, could synergize with dendritic cell vaccines, both in mouse models and patient clinical trials. Interleukin 12 (IL-12) is one of the predominant cytokines released when TLR are activated. In this study, they wanted to see how IL-12 would affect the CD8 T cells.

Graduate student Dominique Lisiero, first author of the study, said CD8 T cells come in a large variety of "flavors" and can be stimulated in differing ways. However, what signals and which stimuli work best to prime the cells to fight cancer was unclear. Lisiero added IL-12 to the CD8 T cells in culture, before the cells were transferred into mice with established brain tumors.

"We wanted to see if we could make these cells become better at either recognizing the tumor or killing tumor cells," she said. "We didn't know what expect, but what we found was that when we programmed these cells in the presence of IL-12, we saw that the tumors decreased in size and the mice with brain metastases survived longer. In fact, Prins said that the mice treated with killer T cells primed in the presence of IL-12 lived about 2.5 times longer than those not receiving the IL-12.

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To better understand the mechanisms by which priming killer T cells in the presence of IL-12 really enhanced their function, the team focused on how these T cells responded to a different cytokine, Interleukin 2 (IL-2). IL-2, which is instrumental for the body's natural response to infection and recognition of foreign invaders, often is included in adoptive transfer immunotherapies to help the T cells survive, but it has to be given in high doses that frequently cause significant toxicity to patients. Prins and Lisiero wanted to know if adding IL-12 would enhance the sensitivity of IL-2 signaling inside the T cells.

"T cells that were primed in the presence of IL-12 had a higher expression of the IL-2 receptor, meaning the T cells had an enhanced ability to respond to the IL-2. This, we believe, allowed the killer T cells to expand and survive after being transferred into mice with brain tumors. " Lisiero said. "Because the IL-12 stimulates the IL-2 receptor, we can give much lower doses of IL-2 and still get the same anti-tumor function from the killer T cells. In patients, this may translate to reduced toxicity. Clinical trials, however, would be required to prove that this priming with IL-12 would have similar effects."

Lisiero also tested the new process on human T cells, culturing them in either IL-2 or IL-12, and studying their function in the lab. The function of the cells programmed in IL-12 was dramatically increased, Prins said, validating the work in the mouse models. Their findings are already influencing how T cells are grown in the lab, he said.

The findings also are translational to the clinic, since metastatic melanoma patients in clinical trials often are removed from the protocol when the cancer appears in their brain. Many oncologists and scientists still believe that T cells can't access the brain because of its immune privilege. This study, however, has proven in a pre-clinical model that these tumors in the brain can in fact be effectively targeted.

"The in vitro priming of mouse tumor-specific CD8 T cells in the presence of IL-12 induced a diverse and rapid anti-tumor effector activity while still promoting the generation of memory cells," the study states. "Importantly, the IL-12-primed effector T cells dramatically reduced the growth of well-established tumors and significantly increased survival to highly immune resistant, established intracranial tumors."

The study was funded by the National Institutes of Health, the Philip R. and Kenneth A. Jonsson Foundations and STOP Cancer.

Source:
UCLA's Jonsson Comprehensive Cancer Center

In my studies, If naive T-Cells differentiate in the presence of IL-12,(secreted from dendritic cells and Macrophage, the cells differentiate into the TH1 phenotype).

“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”

~Charles Darwin~

Take Care,
Jimmy B

Ipilimumab is Working,, Melanoma..Jim Breitfeller

2011-05-06T07:34:00.004-04:00
T-cell Activation!!!!!! Ipilimumab (Yervoy) is working!!!

“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”

~Charles Darwin~
Take Care,

Jimmy B

Dear 16 year Old Me.. Melanoma ..Jim Breitfeller

2011-05-05T09:19:00.001-04:00
Please watch this video, it may save you or a love one.

Spread the word!!!!

Happy Cinco De Mayo

“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”

~Charles Darwin~

Take Care,
Jimmy B

New technique extends cancer-fighting cells' potency in melanoma patients

2011-04-29T10:37:00.000-04:00
New technique extends cancer-fighting cells' potency in melanoma patients

Where did you read this before? Right here!!!! The was a post called A

"Under normal conditions, the reinjected T cells die off in a matter of days. Doctors can increase their staying power by depleting patients' blood of certain regulatory T cells that dampen the anti-tumor T cells' response to cancer or using Interleukin 2, which spurs the growth of T cells.

We are getting so very close to a cure/stabilzation of this diease.

“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”

~Charles Darwin~

Take Care,

Jimmy B

IL-2 Controls the Stability of Foxp3 Expression in TGF-β–Induced Foxp3+ T Cells In Vivo

2011-04-28T14:28:00.005-04:00
IL-2 Controls the Stability of Foxp3 Expression in TGF-β–Induced Foxp3+ T Cells In Vivo

Stimulation of naive CD4+Foxp3− T cells in the presence of TGF-β results in the induction of Foxp3 expression and T suppressor function. However, Foxp3 expression in these induced regulatory T cells (iTreg) is unstable, raising the possibility that iTreg would not be useful for treatment of autoimmune diseases. However, When IL-2 is added, the Foxp3 expression is stabilized.

Why is this important, because the tumors secrete the TGF-β and the activated CD4+ T cells secrete the IL-2 for the propagation of the CD4+ T cells. This is the perfect storm for the tumor. The proliferation and survival the of the Tregs, makes it almost immposible to infiltrate the tumors’s microenviroment.

The Tregs compete for the screted IL-2. Depending on the location and how close the CD4+ T cell to the Tregs, The tregs can gain the upper hand by creating a IL-2 sink.

The Tregs must be neutralized to eliminate the surpressiveness that leads to tolarence of the immune system.

Neutralization of IL-2 or disruption of its signaling by deletion of Stat5 diminished the level of Foxp3 expression resulting in decreased suppressor function of the iTreg in vivo.

Blockade or depleting of the Tregs may be the only way to break the tolarence of the immune system.

“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”

~Charles Darwin~
Take Care,
Jimmy B

Understanding cancer immunotherapy..Melanoma ..Jim Breitfeller

2011-04-03T10:35:00.005-04:00
Understanding cancer immunotherapy
By Dr. NG SOO CHIN

The basic premise of cancer immunotherapy involves enhancing the body’s own immune system to fight off cancer. It sounds logical and simple in concept, but the practice is complicated.

THE need for more effective and targeted therapy for cancer has always been in the minds of researchers and doctors who treat cancer. The traditional methods of treating cancer, ie surgery, radiation, and chemotherapy, have obvious limitations. Surgery would not be effective in disseminated or widespread diseases, while radiation and chemotherapy cause “collateral damage” due to effects on normal cells while killing off cancer cells. Certainly, a treatment modality utilising and enhancing our immune system to prevent or fight off cancer is a sound and attractive concept, hence the basic premise of cancer immunotherapy (CI).

The traditional methods of treating cancer, i.e surgery, radiation, and chemotherapy, have obvious limitations, hence the surge in interest in cancer immunotherapy. There is a general belief that failure of “immune surveillance” is a main contributory cause of cancer arising in an individual. There is also evidence that in many cancer patients, the immune system slows down the growth and spread of tumours. This means we need a competent immune system to prevent cancer, and to prevent it from spreading once cancer has started. The basis of CI, ie enhancing the body’s own immune system to fight off cancer, sounds logical and simple in concept. Unfortunately, like most things in life, the real scenario proves to be far more complicated, and the quest for effective cancer immunotherapy has taken a long time. But slowly and surely, we are unraveling the mysteries.

What are the ‘tools’ of CI?

To battle cancer cells with immunotherapy, we can either stimulate our immune system, or transfer antibodies or T cells from an outside source. Certainly, immunotherapy involving certain cytokines and antibodies has now become part of standard cancer treatment. Other examples of immunotherapy, especially those involving cellular therapy, remain largely experimental. Although many clinical trials of new forms of immunotherapy are in progress, an enormous amount of research and clinical trials need to be done before the findings can be widely applied.

What are the different types of CI available now?

The cytokines and monoclonal antibodies used are not called drugs or medication, but are labeled as biological immune response modulators (BIRMs), which include cytokines such as interferons, interleukins, colony-stimulating factors and monoclonal antibodies, plus cancer vaccines. We can further categorise them as below:

I. Immunostimulants

Immunostimulants are non-specific agents that tune-up the body’s immune defences. There have been some success with interleukin-2 (IL-2), a potent growth factor for T cells, which have been used in kidney and malignant melanoma, while alpha-interferon (IFN) are used for the treatment of chronic myeloid leukaemia and hairy cell leukaemia.

II. Monoclonal antibodies

Monoclonal antibodies are identical because they are produced by one type of immune cell – all clones of a single parent cell. Currently, most of the antibodies used are produced by recombinant DNA technology. The basis of monoclonal therapy is that different tumours have unique tumour antigens on their surfaces, and the identification of such antigens, such as CD20 on lymphoma cells, and the production of anti-CD20 antibody, ie rituximab, enables a targeted hit on the tumours. This will result in selective killing of lymphoma cells. Indeed, the advent of rituximab has changed the landscape of lymphoma treatment, with improvement in response and survival of patients. Similarly, other monoclonal antibodies such as herceptin (breast cancer), bevacizumab (lung cancer), and alemtuzumab (chronic lymphocytic leukaemia) are making waves in cancer treatment.

III. Immunotoxins and radioimmunotherapy

Monoclonal antibodies can be modified for delivery through toxin, radioisotope, cytokine or other active conjugates. Many such conjugates have been tried with some success. Mylotarg was licensed by the US Food and Drug Administration (FDA) for treatment of acute myeloid leukaemia (AML). Myelotarg is a combination of anti-CD33 and calicheamicin (a cytotoxic compound). However, it was recently withdrawn from the market due to potential severe liver damage. Monoclonal antibodies against tumour antigens can also be coupled to radioactive atoms. The goal with these agents is to limit the destructive power of radiation to those cells (cancerous) that have been “tagged” by the attached monoclonal antibody. Zevalin is a monoclonal antibody against the CD20 molecule on B cells (and lymphomas) conjugated to the radioactive isotope yttrium-90 (90Y). The results in treating B cell lymphoma with radioimmunotherapy are encouraging, though the delivery of such an agent is somewhat cumbersome.

IV. CI with T Cells (allografts or autografts of T cells)

T lymphocytes such as cytotoxic T lymphocytes (CTL) are capable of killing target or tumour cells. How to prime them to act appropriately, ie to kill tumour cells and not other normal cells, remains the challenge. The main reason why allogeneic bone marrow transplants (allografts) work is because of the the post transplant continual attacks on the tumour cells by T cells (graft versus tumour effect) seen in many patients. However the accompanying graft versus host reaction can be severe enough to result in significant mortality and morbidity to the transplant recipient. The same effect of such immunological attacks on tumour cells can be harnessed by donor lymphocyte infusion. This is a double edged sword and needs to be used with extreme caution. Infusion of own or autologous T cells or genetically modified T cells have been attempted with limited success.

V. Cancer vaccines

The response of the patient’s own immune system – immune surveillance – has clearly failed in cancer patients. The purpose of cancer vaccines is to elicit a more powerful active immunity in the patient. Several approaches are being explored. The name “cancer vaccines” is somewhat misleading, as these vaccines are developed to cure cancer and not to prevent it. Dendritic cells (DC) are the most potent antigen-presenting cells. They engulf antigens, process them into peptides, and “present” them to T cells. The making of the vaccine entails, firstly, harvesting DC from patients and exposing them to tumour specific antigens. By injecting the “stimulated” DC back to the body, they may be able to elicit a strong immune response and attack the tumour, utilising the stimulated cytotoxic T lymphocytes. On April 29, 2010, the FDA approved the first anti-cancer vaccine, a patient-specific dendritic cell vaccine for use against advanced prostate cancer. Tumour-antigen specific vaccines are used to immunise the patient with an antigen universally expressed by tumours of that type (but not by normal cells), mixed with some form of adjuvant that will enhance the response. Unlike patient-specific vaccines, these vaccines can be mass-produced for use in anyone with the appropriate tumour.

What are the strengths of immunotherapy?

The most appealling point of CI is that potentially, this is a targeted therapy, and hence the side effects to normal cells would be considerably less. Some chronic myeloid leukaemia patients with relapsed disease post-bone marrow transplant managed to attain long term survival after donor lymphocyte infusion. CI is a very powerful tool indeed, if only we know how to apply it optimally, but we are still grappling how best to titrate the graft versus leukaemia response. Because the side effects are different from conventional chemotherapy, the combination of cytotoxics and immunotherapeutic agents such as rituximab has improved the outcome in lymphoma patients without additional side effects. Because of the favourable safety profile, CI can be given in repeated courses, unlike cytotoxics, which are limited by their cumulative toxicities.

What are the weaknesses or problems of immunotherapy?

The main problem is likely to be the need for time for the immune system to respond to CI, and in some patients with cancer which behaves like a runaway train, eg Burkitt’s lymphoma, time is what the patients do not have. CI is unlikely to work in a large volume tumour, and the tumour needs to be debulked (reduced in size) before CI has a chance to work. CI is costly, and the price is not likely to go down in the near future. Monoclonal antibodies are fabulously expensive. This is even so for a personalised vaccine. For patients who have financial constraints, money is not everything – it is the only thing! Hence, it is likely that such treatment may not be available to those who need it, unless some assistance programme is forthcoming. It is unlikely that CI alone can cure a cancer in the setting of cancer patients whose immune systems have failed them in the first place. We need to learn and strategise how to put different treatment modalities, ie chemotherapy, CI, radiotherapy, in a winning treatment combination. The answer can only come with more painstaking research and careful clinical trials.

Is immunotherapy devoid of side effects?

A resounding NO. Any form of treatment can potentially give rise to side effects. Even taking paracetamol can cause severe allergic reactions, although rarely. Rituximab commonly gives rise to infusion reactions, which are manageable. In 2006, in one of the phase 1 trials of a T cell stimulatory monoclonal antibody called TGN1412 in England, all six of the volunteers were nearly killed, and ended up with multiple organ damage due to unrestrained generalised T cell stimulation. So forget about the no side effects talk. I believe the side effects of immunotherapy are different from conventional treatment like chemotherapy, and we have to learn about them (both short term and long term), and deal with them accordingly. For instance, we now know that the use of chemo-immunotherapy in treating non-Hodgkin’s lymphoma can cause potentially fatal hepatitis B virus activation. This problem is prevented by concurrent antiviral therapy. How does CI fit into a patient’s treatment plan? Can a patient ask for immunotherapy first before following established treatment or can CI be the sole form of treatment? I feel the best person to answer the question is the oncologist/haematologist who is looking after the patient. CI with monoclonal antibodies can be used in induction (initial treatment) or to consolidate the treatment, and in some instances, to remove any minimal residual disease. Cell-based immunotherapy remains experimental and is likely to be offered in a setting of clinical trials. Very rarely is CI used as the sole form of therapy. I honestly feel that clinicians should make the decision. Using inappropriate therapy results in loss of valuable time in tackling the cancer, not to mention the accompanying financial toxicity!

What are the basic questions to ask when one checks out immunotherapy?

The patient really needs to know what he or she is in for. Is the centre a reputable one, and is the treatment approved by authorities such as the FDA or EU (European Union)? Is the treatment potentially curative or merely palliative? Are there other treatment options which may work just as well? What does the procedure entail and what are the potential side effects? The patient, together with the attending doctor, should weigh the benefit versus risk equation, and also the cost effectiveness of the planned treatment. In other words, one should go into any treatment only with eyes widely open. When a treatment sounds too good to be true, it usually is.

Is CI ready for prime time?

It is important to keep our feet firmly on the ground and not be taken by sales propaganda. In some forms of CI, such as monoclonal antibodies treatment, many lives are prolonged and saved, and monoclonal antibodies is now an established treatment modality. We need to tread far more carefully in cell based therapy. To date, the FDA has only approved one, and only one, cancer treatment vaccine, i.e. Provenge (sipuleucel-T). The vaccine is designed for men with advanced prostate cancer who have limited treatment options. Patients will have immune cells purified from their blood, and then combined with a specific protein (an antigen) that stimulates the immune cells to recognise and kill prostate cancer cells. The custom created vaccine is given intravenously in three doses, two weeks apart. Potential reactions include fever and flu-like symptoms. Before we get carried away, the new treatment resulted in a very modest 4.1 month improvement in median survival compared to the placebo group.

Why the surge in interest in CI?

According to the American Cancer Society, immunotherapy, especially cancer vaccines, is still a small field which hasn’t yet proven itself to be better than other types of cancer treatments. However, it’s one that researchers say holds a lot of promise and “many future advances against cancer will probably come from this field”. Interestingly, Time magazine voted in two cancer researchers, Dr Larry Kwak and Dr Doug Schwartzentruber, for its 2010 list of 100 most influential people in the world. Both of them are in the forefront of cancer vaccine research. Dr Kwak is involved in BiovaxID patient-specific vaccine for follicular lymphoma while Dr Schwartzentruber is researching a melanoma vaccine. Both vaccines had good phase 3 trial results and may make their way to bedside use soon. Is there a need for regulation of CI in Malaysia? The answer has to be yes. Unfortunately, we have no shortage of entrepreneurs, and for new therapies, whether it’s stem cell based or cell based, medical supervision is necessary to protect our patients. We don’t want to make news for the wrong reasons. At the end of the day, we should heed Hippocrates’ wise words – to cure sometimes, to comfort always, and not to cause any harm to our patients. This article is contributed by The Star Health & Ageing Panel, which comprises a group of panellists who are not just opinion leaders in their respective fields of medical expertise, but have wide experience in medical health education for the public.

The members of the panel include:

Datuk Prof Dr Tan Hui Meng, consultant urologist; Dr Yap Piang Kian, consultant endocrinologist; Datuk Dr Azhari Rosman, consultant cardiologist; A/Prof Dr Philip Poi, consultant geriatrician; Dr Hew Fen Lee, consultant endocrinologist; Prof Dr Low Wah Yun, psychologist; Datuk Dr Nor Ashikin Mokhtar, consultant obstetrician and gynaecologist; Dr Lee Moon Keen, consultant neurologist; Dr Ting Hoon Chin, consultant dermatologist; Prof Khoo Ee Ming, primary care physician; Dr Ng Soo Chin, consultant haematologist.

For more information, e-mail starhealth@thestar.com.my. The Star Health & Ageing Advisory Panel provides this information for educational and communication purposes only and it should not be construed as personal medical advice. Information published in this article is not intended to replace, supplant or augment a consultation with a health professional regarding the reader’s own medical care. The Star Health & Ageing Advisory Panel disclaims any and all liability for injury or other damages that could result from use of the information obtained from this article.

Source: http://thestar.com.my/health/story.asp?file=/2011/4/3/health/8389839&sec=health

“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”

~Charles Darwin~

Take Care,
Jimmy B

Imagining a Cure..Melanoma ..Jim Breitfeller

2011-04-02T10:45:00.004-04:00
Imagining a Cure
By Nicholas P. Restifo and Megan Bachinski
For cancer patients, close is not good enough.

Andrzej KrauzeImagine a land where every year a deadly plague afflicts 53,000 people—enough to fill a small stadium. Most are fortunate enough to discover their illness early, when it is completely curable. But 8,000 are not so lucky and their disease spreads to other parts of the body, with lethal consequences. Imagine this happening each year, with little reduction in the numbers who die, and you will understand the toll melanoma takes on patients and their families in the United States alone.

An electrical switch for cancer?

Currently, there are only two FDA-approved treatments for patients with metastatic melanoma: dacarbazine and interleukin-2. These treatments have complete response rates of 2.7 percent and 6.3 percent respectively. A durable complete response—the disappearance of all cancer—is the holy grail of cancer treatment. While patients can sometimes benefit enormously from partial responses, every patient aspires to become cancer free. Studies have shown that in the case of metastatic cancer, any residual tumor cells not killed by therapeutic intervention will ultimately grow back.

Two new treatments, ipilimumab and PLX4032, will probably soon receive FDA approval. While both improve the survival of late-stage metastatic melanoma patients, their reported rates of durable complete response are 0.6 percent and about 2.0 percent, respectively. The difficult reality for melanoma patients is that partial response with any of the available treatment offers only a temporary respite in disease progression. Of course, living with cancer is better than dying from it, but oncologists have not yet been able to achieve a “stasis” of disease like that seen in patients with HIV. Although there are exceptions, delays in the progression of metastatic melanoma after an incomplete response to treatment are usually measured in months, not years, and most of these patients will die from their disease.

A durable complete response—the disappearance of all cancer—is the holy grail of cancer treatment.Adoptive cell transfer (ACT) might offer more than simply hope to people who have failed on these and other treatments. ACT employs methods that involve extracting a patient’s antigen-specific immune cells, usually found in tumor tissue, and expanding the number of these antitumor T lymphocytes ex vivo. When the cells are reinfused intravenously together with the T-cell growth factor (interleukin-2), they are demonstrably capable of trafficking to the tumor and mediating its destruction. The addition of “preparative lymphodepletion”—the temporary ablation of a cancer patient’s immune system—can be accomplished using chemotherapy alone or in combination with total-body irradiation, and is associated with enhanced persistence of the transferred T cells.

ACT can lead to prolonged tumor eradication even for patients with stage IV metastatic melanoma who have exhausted other treatment options. While oncologists are always hesitant to use the word “cure,” mature clinical trials of ACT have demonstrated the disappearance of all tumor in 20/93 patients treated (21.5%). Most importantly, for 19 of these 20 patients (95%), the complete responses have been durable and long-lasting, with some patients remaining disease free for more than 7 years (J Clin Oncol, 26:5233-39, 2008; updated 2010). For these patients, ACT-based immunotherapy may well represent a cure.

It is not easy to own the “drug” used in adoptive cell transfer— the patient’s own T cells.It is important to distinguish ACT-based treatments from other immunotherapies, such as therapeutic cancer vaccines, which have seen a surge of support from pharmaceutical companies since the approval of sipuleucel-T (Provenge). Costing approximately $93,000, sipuleucel-T is not associated with long-term response or even tumor regression. Cancer vaccine clinical trials have resulted in an overall response rate of less than 4 percent (Immunol Rev, 239:27-44, 2011). Some therapeutic cancer vaccines might provide modest but valuable prolongation of survival, but those currently in use do not come close to the aspirational goal of a “cure.”

If ACT-based immunotherapies have the potential to cure one in five patients with metastatic melanoma, why is the procedure only available in a handful of locations worldwide? Why is there so little commercial interest in developing this therapy? What can be done to facilitate the more widespread administration of ACT-based immunotherapies?

The first explanation for the scarcity of these treatments is financial. ACT-based immunotherapies are still considered experimental, are not FDA-approved, and are not paid for by patients’ insurance. Thus, only a handful of locations are able to bear the fiscal burden of administering ACT. But how heavy is that burden? Assuming the host institution has a cell production facility and the specialized staff to run it, the cost for producing a single dose of adoptively transferred T cells is approximately $20,000 plus all costs associated with hospitalization for the treatment. However, even though the costs of ACT can be high, most patients only require a single dose. Estimated costs seem comparable to or less expensive than many of the recently FDA-approved cancer medications—such as bevacizumab (Avastin) or cetuximab (Erbitux)—where the price tag for the medicine alone can exceed $80,000, and no patients are cured. Although ACT-based immunotherapies are neither quick nor cheap, an immune-based approach this effective for a subset of patients is likely to represent a reasonable cost-benefit profile.

It might seem perplexing that the private sector has not pushed for an FDA-approved licensing trial. However a clear path to profitability is still missing in the development of ACT-based immunotherapy for use in the medical marketplace. Not a simple injection or a pill, ACT-based treatments are uniquely tailored for each patient. The cost of entry into the field with a licensing trial includes construction of a specialized facility and the acquisition of highly trained medical and laboratory staff. There may also be a perception that ACT-based approaches lack a clearly defined claim to intellectual property (IP), which entices companies and their shareholders to invest in the development of new treatments. After all, it is not easy to own the “drug” used in ACT—the patient’s own T cells. However, recent financial success realized by Dendreon, the manufacturers of Provenge, which also uses autologous cells, may go a long way toward changing the attitudes of investors. Many aspects of antitumor T cell production might be patentable, and the use of patentable genetically engineered T cells could provide the type of clearly defined IP that investors seek.

Some may argue that a more appropriate sponsor for ACT-based immunotherapy is the cash-strapped public sector. It seems more likely that a network of cancer centers, institutes, and hospitals could form a consortium to refine ACT technology and sponsor an FDA-approved licensing trial. A successful trial and FDA approval for ACT-based immunotherapy could result in a financial windfall for participating institutions. It also seems plausible that leaders from the not-for-profit sector could step forward. A social entrepreneur or “dot-org” research foundation could potentially catalyze the widespread application of ACT technology.

Adding to the list of cancers treatable with ACT could provide a new group of stakeholders with the impetus to push the concept forward. Although most of the work done thus far has been focused on melanoma, current efforts have enlarged the list of cancers treatable with ACT to include synovial-cell sarcomas and B-cell lymphomas. These new examples will hopefully encourage corporate and nonprofit entities to envision the possibility of treating more-common cancers, such as those of the lung, breast, colon and prostate, which offer bigger targets for cure, as well as larger financial incentives. Although the use of ACT-based treatments remains confined to a handful of centers worldwide, the employment of a patient’s own immune system to eradicate cancer is a strategy that can no longer be ignored.

Nicholas P. Restifo is a principal investigator at the National Cancer Institute’s Center for Cancer Research, where he works on designing new immunotherapies for patients with advanced cancer. Megan Bachinski is a writer and editor living in Silver Spring, Maryland.

Read more: Imagining a Cure - The Scientist - Magazine of the Life Sciences http://www.the-scientist.com/article/display/58067/#ixzz1INPptwuK

Instead of using ACT therapy (Growing the cells outside body in flasks), What if you did it in vivo. (Inside the Body) This can be done with Combinatorial Therapy with the help of the newly approved Yervoy (Ipilimumab) and Interluekin-2.

Melanoma and the Magic Bullet (Monoclonal Antibodies)

Click on for a copy of Melanoma and the Magic Bullet

“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”
~Charles Darwin~
Take Care,
Jimmy B

A call for patients that failed PLX-4032 Melanoma Jim Breitfeller

2011-03-29T19:06:00.003-04:00
Genentech has just opened a study for people who have taken the Plexxikon/Roche/Genentech BRAF inhibitor, also known as PLX 4032. This study is a combination trial using PLX plus a MEK inhibitor. Some folks from this board have been in the BRAF/MEK trial being run by GSK, and this new trial is similar. One criteria, though, is that you must have taken the Plexxikon drug and have developed resistance to that drug. Currently three sites are open: Dr. Gajewski in Chicago, Dr. Ribas in UCLA, and Dr. Gonzalez in Denver. Four more sites will open soon. You can go to this link to find out information about melanoma relevant clinical trials, including this one: http://www.emergingmed.com/networks/MRF

Source: Tim--MRF

“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”

~Charles Darwin~

Take Care,

Jimmy B

Profitable are the sick, for they shall be exploited..Melanoma..BMS ..Jim Breitfeller

2011-03-26T20:35:00.000-04:00
Profitable are the sick, for they shall be exploited

I know many Melanoma Patients turned away by Bristol Myer Squibb.

“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”

~Charles Darwin~
Take Care,

Jimmy B

F.D.A. Approves Drug to Treat Melanoma..Jim Breitfeller

2011-03-25T15:09:00.003-04:00
The FDA just announced that they have approved Yervoy "ipi" for unresectable and metastatic melanoma. This is the first time a drug has been approved for melanoma in 13 years, so great news!

Here's the announcement:

FDA NEWS RELEASE

For Immediate Release: March 25, 2011

Media Inquiries: Erica Jefferson, 301-796-4988, erica.jefferson@fda.hhs.gov

Consumer Inquiries: 888-INFO-FDA

FDA approves new treatment for a type of late-stage skin cancer

Melanoma patients lived longer with treatment

The U.S. Food and Drug Administration today approved Yervoy (ipilimumab) to treat patients with late-stage (metastatic) melanoma, the most dangerous type of skin cancer.

Melanoma is the leading cause of death from skin disease. An estimated 68,130 new cases of melanoma were diagnosed in the United States during 2010 and about 8,700 people died from the disease, according to the National Cancer Institute.

"Late-stage melanoma is devastating, with very few treatment options for patients, none of which previously prolonged a patient's life," said Richard Pazdur, M.D., director of the Office of Oncology Drug Products in the FDA's Center for Drug Evaluation and Research. "Yervoy is the first therapy approved by the FDA to clearly demonstrate that patients with metastatic melanoma live longer by taking this treatment."

Yervoy is a monoclonal antibody that blocks a molecule known as cytotoxic T-lymphocyte antigen or CTLA-4. CTLA-4 may play a role in slowing down or turning off the body's immune system, affecting its ability to fight off cancerous cells. Yervoy may work by allowing the body's immune system to recognize, target, and attack cells in melanoma tumors. The drug is administered intravenously.

Yervoy's safety and effectiveness were established in a single international study of 676 patients with melanoma. All patients in the study had stopped responding to other FDA-approved or commonly used treatments for melanoma. In addition, participants had disease that had spread or that could not be surgically removed.

The study was designed to measure overall survival, the length of time from when this treatment started until a patient's death. The randomly assigned patients received Yervoy plus an experimental tumor vaccine called gp100, Yervoy alone, or the vaccine alone.

Those who received the combination of Yervoy plus the vaccine or Yervoy alone lived an average of about 10 months, while those who received only the experimental vaccine lived an average of 6.5 months.

Common side effects that can result from autoimmune reactions associated with Yervoy use include fatigue, diarrhea, skin rash, endocrine deficiencies (gland or hormone), and inflammation of the intestines (colitis). Severe to fatal autoimmune reactions were seen in 12.9 percent of patients treated with Yervoy.When severe side effects occurred, Yervoy was stopped and corticosteroid treatment was started. Not all patients responded to this treatment. Patients who did respond in some cases did not see any improvement for several weeks.

Due to the unusual and severe side effects associated with Yervoy, the therapy is being approved with a Risk Evaluation and Mitigation Strategy to inform health care professionals about these serious risks. A medication guide will also be provided to patients to inform them about the therapy's potential side effects.

Yervoy is marketed by New York City-based Bristol-Myers Squibb.

For more information:

FDA: Office of Oncology Drug Products

http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm091745.htm

FDA: Approved Risk Evaluation and Mitigation Strategies (REMS)

http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm111350.htm

FDA: Approved Drugs: Questions and Answers

http://www.fda.gov/Drugs/ResourcesForYou/Consumers/ucm054420.htm

NCI: Melanoma

http://www.cancer.gov/cancertopics/types/melanoma

CDC: Skin Cancer

http://www.cdc.gov/cancer/skin/

“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”
~Charles Darwin~
Take Care,
Jimmy B

Late-Breaking Abstracts..Melanoma ..Jim Breitfeller

2011-03-24T13:39:00.003-04:00
Late-Breaking Abstracts
2010 Annual Meeting; Washington, D.C., October 2-4, 2010 3
International Society for Biological Therapy of Cancer (iSBTc; now known as the Society for Immunotherapy of Cancer; SITC)
-162-

USING TIMING TO SYNCHRONISE IMMUNOTHERAPY THROUGH
MICROMANIPULATION OF THE UNDERLYING TUMOR IMMUNE RESPONSE:
FROM COLEY TO ROSENBERG, LOTZE, ALLISON, WOLCHOK AND BEYOND!

Brendon J. Coventry1, Martin L. Ashdown2, Svetomir N. Markovic3
1Surgery and Immunology, University of Adelaide, Adelaide, SA, Australia
2Medicine, University of Melbourne, Melbourne, VIC, Australia
3Medical Oncology, Mayo Clinic, Rochester, MN

Introduction: Immunotherapy studies in advanced cancers appear to show that the immune
response can be driven in either an ‘effector’ or ‘regulatory’ direction or a ‘mixture’ of these,
leading to the heterogeneous clinical responses (CR, PR, PD) seen. Using CRP as a marker, we
have shown that a repeating cyclical, dependent, sequential, orchestrated, homeostatic
physiologic process appears to be occurring in most, if not all, cancer patients, most likely as a
result of chronic antigenic stimulation. The correct timing of immunotherapy or chemotherapy
with this ‘immune cycle’ appears to be associated with better cancer control and improved
clinical outcomes.
We are concerned that the timing of therapy with respect to the underlying tumor immune
response fluctuations is the principal determinant of efficacy in cancer treatment. The
observations and model may also extend to other chronic inflammatory states to determine
therapeutic efficacy.

Methods: Using serial CRP measurements in late-stage cancer patients, we have recently been
able to expose sequential and time dependent oscillations in the inflammatory/ immune response
that may represent a homeostatic, repeating or cyclical process of tumour immune
responsiveness then tolerance. The periodicity of these cycles appears to be reproducible at
approximately 6-7 days.
By serially measuring CRP around the time of vaccination or chemotherapy, the position on the
underlying immune curve can be established. Timing with respect to this cycle appears to be
critical to modulating the immune system with each intervention, and pivotal to the clinical
efficacy of therapy (1,2).

Results: Using these methods, we have been able to correlate the timing of vaccination/
chemotherapy with the induction of clinical responses. Induction of complete responses, stable
disease, slowed growth even with persistent metastatic disease, appears possible using these
principles, thereby improving overall survival.

Conclusions: The historical ‘random successes’ seen with vaccines, cytokines and receptor
directed monoclonal antibodies may be due to their fortuitous accidental interference with the
underlying persistent, homeostatically regulated tumor immune kinetics by their ‘random’
untimed administration. By accurately and appropriately synchronizing therapy to each patient’s
immune system’s periodic oscillations - immune cycle - we predict that the current low random
immunotherapy successes seen to date, can be made more predictable by accurately timing
therapy better, and will achieve greater clinical efficacy.

Where have you heard the key to an immune response is dose and timming.

Right Here

Melanoma and the Magic Bullet
The Research paper called Melanoma and the Magic Bullet

The Research paper called The Making of an Immune Response by Combinatorial Therapy Using Anti-CTLA-4 Blockade and Interleukin-2

“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”
~Charles Darwin~
Take Care,
Jimmy B

Bristol-Myers Awaits Approval for Drug's New Cancer Attack

2011-03-22T10:56:00.000-04:00
With This FDA Approval, This is the begining of the end cancer as we know it. Ipilimumab will revolutionize Cancer therapy along with Anti-PD-1 and HD IL-2.

Bristol-Myers Awaits Approval for Drug's New Cancer Attack

“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”
~Charles Darwin~
Take Care,
Jimmy B

Sounding the Danger Signal through chemotherapy to Cause Cancer Cell Death..Melanoma ..Jim Breitfeller

2011-03-17T13:24:00.009-04:00
Sounding the Danger Signal through chemotherapy to Cause Cancer Cell Death

“Schedule and Dose for Combination Therapy,”
2011 Scientific Colloquium of the Cancer Immunotherapy Consortium

Thursday, March 17, 2011 7:00 AM - Saturday, March 19, 2011 1:30 PM
Eastern Time

Dr. Hy Levitsky is introducing Dr. Laurence Zitvogel from Institut Gustave Roussy, a leader in cell biology in cancer.

New Speaker: Laurence Zitvogel, Ph.D.

Institut GustaveRoussy, Villejuif, France

"Dr. Zitvogel graduated in medical oncology from the School of Medicine of the University of Paris in 1992. She started her scientific career when she was at the University of Pittsburgh in Michael Lotze’s laboratory. She became research director at Institut National de la Santé et Recherche Médicale in a laboratory located at Institut Gustave Roussy, a large cancer center in Villejuif, France, and the head of the Center for Clinical Investigations for vaccine developments at Villejuif. Dr. Zitvogel has been actively contributing to the field of cancer immunology and immunotherapy, bringing together basic and translational research, including the design of cancer therapies through combined animal studies and phase I patient trials. Her expertise is mainly dendritic cell and innate effector biology and relevance during tumor development, as well as exosome-based vaccine designs."

Zitvogel: chemotherapy may work because cancer cell death is immunogenic and triggers anti-cancer immunity

Zitvogel: Chemo causes cancer to express "eat me" or "come and get me" signals to the immune system. Nice way to phrase it!

Jimmy B: See Graph Below

Autophagy Defintion: The process of self-digestion by a cell through the action of enzymes originating within the same cell.

Zitvogel: "autophagy" is important to death of cancer cells. It breaks down in cancer growth. Chemo re-starts the autophagy process.

Zitvogel: some types of chemo are better at inducing immunogenic cell death than others. Cisplatin and taxols aren't strong in this.

Zitvogel: new tests can show how a drug falls short in triggering immunogenic cancer death -- and how to compensate for that.

Zitvogel: Giving thapsigarin can improve cisplatin's ability to trigger immunogenic cancer cell death.

Jimmy B: Thapsigargin sensitizes human melanoma cells to TRAIL-induced apoptosis

Zitvogel: "drug repositioning" is the process of combining drugs to compensate for where one falls short in immunogenic cell death.

Zitvogel: combining immunogenic chemotherapies with immunomodulators or other immunotherapy is a very promising strategy.

Source: Cancer Research on Twitter

http://twitter.com/#!/search?q=%23cic11

“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”

~Charles Darwin~

Take Care,
Jimmy B

“Schedule and Dose for Combination Therapy,” Melanoma.. 2011 Scientific Colloquium of the Cancer Immunotherapy

2011-03-17T09:54:00.012-04:00
“Schedule and Dose for Combination Therapy,”
2011 Scientific Colloquium of the Cancer Immunotherapy Consortium
• Thursday, March 17, 2011 7:00 AM - Saturday, March 19, 2011 1:30 PM
Eastern Time

First Speaker: Dr. Rafi Ahmed
Director of the Emory Vaccine Center

"As a basic immunologist, EVC Director Dr. Rafi Ahmed studies immunological memory – the ability of the immune system to “remember” a particular antigen and respond accordingly. Dr. Ahmed and his colleagues have made significant discoveries about how immune memory cells are created and how long they survive; understanding these mechanisms is crucial to the development of vaccines for HIV and other infectious agents. In addition to contributing vitally to vaccine science, Dr. Ahmed’s findings are being applied to research into therapies for the treatment of cancer and the prevention of organ rejection."

Dr. Rafi Ahmed is now being introduced by Johannes Vieweg, & highlighting his work on immunological memory

Dr. Ahmed is sharing how lessons from immune memory development in chronic viral infection can inform cancer immunotherapy field

Ahmed: wait 30-60 days to boost in vaccination produces better immune responses for many types of viral vaccines. Same for cancer?

JimmyB :Why 30 to 60 days? Because this is the time factor that it takes for the CD4+ and CD8+ T-cells to grow and differentiate into effector T-cells. (See Graph)

Fig-1

Dr. Rafi Ahmed is now being introduced by Johannes Vieweg, & highlighting his work on immunological memory Dr. Ahmed is sharing how lessons from immune memory development in chronic viral infection can inform cancer immunotherapy field Ahmed: wait 30-60 days to boost in vaccination produces better immune responses for many types of viral vaccines. Same for cancer?
Fig-2

Ahmed: Synergy we've seen combining PD-1 with IL-2 (negative + positive signal) in viral infection therapy have been astonishing.

Jimmy B:Imagine if you combine CTLA-4 + PD-1 and IL-2. The Holy Grail of Immuno therapy I believe.

Ahmed raises point that mTOR inhibition may enhance vaccine-induced memory CD8 T-cells. Role for combining with cancer vaccines?

Much audience Q&A for Dr. Ahmed - when see exhaustion clinically, is it inhibition, effect of dose of IL-2, and role of autophagy?

Source: Cancer Research on Twitter

http://twitter.com/#!/search?q=%23cic11

“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”
~Charles Darwin~
Take Care,

Jimmy B

Interviews with Laurie and Bob from Melanoma ROADTRIP..Jim Breitfeller

2011-03-04T08:05:00.005-05:00
Interviews with Laurie and Bob from Melanoma ROADTRIP

CP:boblawrencesjourney

boblawrencesjourney

“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”
~Charles Darwin~
Take Care,
Jimmy B

Breakthrough Drugs Target Deadly Cancer - Boston News Story - WCVB Boston

2011-03-01T14:16:00.000-05:00
Combination Therapy BRAF + MEK
When it works, it works quite well.

Breakthrough Drugs Target Deadly Cancer - Boston News Story - WCVB Boston

“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”
~Charles Darwin~
Take Care,
Jimmy B

A Melanoma Story,.. Read the Comments. BMS denies Compassionate Care to a dying patient.. Jim Breitfeller

2011-02-24T07:59:00.007-05:00
A Melanoma Story,.. Read the Comments. BMS denies Compassionate Care to a dying patient. It is an EYE OPENER!!!!!!

-And-thats-all-I-know

Read the 62+ comments from the comments link at the top of the page.

Bristol Myer Squibb should be held accountable for it's actions.

“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”
~Charles Darwin~
Take Care,
Jimmy B

Melanoma Road Trip with Jay Allen and Clint from down-Under..Jim Breitfeller

2011-02-18T14:21:00.000-05:00
Check out two Survivors of Melanoma Tour The USA

Home

“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”
~Charles Darwin~
Take Care,
Jimmy B

Tumor immunity: The Goldilocks approach.. Melanoma..jim Breitfeller

2011-02-16T07:33:00.001-05:00
Tumor immunity: The Goldilocks approach

“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”
~Charles Darwin~
Take Care,

Jimmy B

The hormone that holds key to HIV cure may also Help in Melanoma Therapy..Jim Breitfeller

2011-02-06T16:07:00.006-05:00
The hormone that holds key to HIV cure may also Help in Melanoma Therapy.

The hormone that holds key to HIV cure may also shift the balance of the immume system to activation. By increasing the Hormone IL-7 during therapy, you could shut down the SOCS3 expression giving rise to the TH1 Phenotype needed for the immune response.

Source:The hormone that holds key to HIV cure

“The researchers increased levels of the hormone IL-7, the gene SOCS-3 “switched off” and the trial mice were able to gradually eliminate the HIV from their bodies, says the main study published in the February 4 2011 issue of the journal Cell.”

SOCS3 inhibits TH1 Phenotype
SOCS3 inhibits TH17 Phenotype
SOCS3 activates TH2 phenotype

Is it possible by the raising the IL-7 concentration, pushes the T-cell differentiation towards the TH1/TH17 phenotypes. If that is the case, the oncologists have another knob to turn to involke an immune response.

“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”

~Charles Darwin~

Take Care,

Jimmy B

Immunotherapeutic Barriers at the Level of the Tumor Microenvironment..Melanoma .Jim Breitfeller

2011-02-04T15:20:00.013-05:00
Last year I Blogged about the Missing Link in T-cell activation with a vaccine. We were missing the Proflammatory Cytokines that produce the "Danger Signal" to the Immune system. Well Dr. Gajewski has come out and has backed up my theory.

Along with that, there are Two companies that are persuing this theory with Cytokine Therapy.

Thomas F. Gajewski, MD, PhD (University of Chicago) presented on the key role that the tumor microenvironment plays in determining the outcome of a tumor immune response. He noted the complexity of the tumor with respect to its structural and cellular composition and that the functional phenotypes of these cells may or may not permit an effective anti-tumor response at either the priming or effector phase. Characteristics of the tumor microenvironment may dominate during the effector phase of an anti-tumor T cell response, limiting the efficacy of current immunotherapies by inhibiting T cell trafficking into the tumor, eliciting immune suppressive mechanisms within the tumor, altering tumor cell biology and susceptibility to immune-mediated killing, or modifying the tumor stroma (i.e., vasculature, fibrosis). These features can be interrogated through pre-treatment gene expression profiling of the tumor site in individual patients; such an analysis may identify a predictive biomarker profile associated with clinical response. This strategy may also help identify biologic barriers that need to be overcome to optimize therapeutic efficacy of vaccines and other cancer immunotherapies. Mouse models have helped to define the hallmarks of an anti-tumor response, taking into account the effector phase within the tumor microenvironment. Based on these models, a DC subset (CD8α+) appears necessary for priming of host CD8+ T cells through cross-presentation of antigen within the draining lymph node. Antigen specific naïve CD8+ T cells that recognize the antigen within the lymph node and receive appropriate co-stimulatory and proliferative signals acquire their effector phenotype. In order to assert immune control over the tumor, these effector CD8+ T cells must enter the bloodstream, and via chemokine signals, traffic to the tumor site; once there, these T cells must overcome immune regulatory/suppressive mechanisms. In a small study of an IL-12-based melanoma vaccine, Dr. Gajewski and colleagues correlated pre-treatment biopsy gene expression to outcomes and noted that in responding patients, tumors expressed chemokines (e.g., CXCL9 which binds CXCR3 on activated CD8+ T cells), which in some instances were able to recruit T cells into the tumor site. A broader transcript analysis of banked melanoma tissue demonstrated a subset of tumors with T cell markers co-associated with a panel of chemokines. Among responders in the vaccine trial, there was a pattern of expression of T cell- recruiting chemokines, T cell markers, innate immune genes, and type I IFN—all of which indicate productive inflammation. These results were supported by other cancer vaccine studies that demonstrated a strong correlation between survival and the expression of T cell markers and chemokines within the tumors. The results from these gene expression studies may be useful in identifying biomarkers that could provide valuable information for selecting patients most likely to respond to immunotherapies. Additionally, these studies point toward specific strategies for overcoming immunologic barriers to immunotherapy at the level of the tumor microenvironment. Thus, based on gene expression profiling, tumors can be categorized as T cell poor tumors, which lack chemokines for recruitment and have few indicators of inflammation, and T cell rich tumors, which express T cell recruiting chemokines, contain CD8+ T cells in the tumor microenvironment, and have a broad inflammatory signature. A strong presence of T cells within the tumor is predictive of clinical benefit from vaccines.

These observations prompt several important questions:

1) What dictates recruitment of activated CD8+ T cells into the tumor?
2) Why are tumors with CD8+ T cells not spontaneously rejected?
3) What are the innate immune mechanisms that promote spontaneous T cell priming in a subset of patients?
4) What oncogenic pathways in tumor cells drive these two distinct phenotypes?

Studies of CD8+ T cell recruitment to the tumor site point to a panel of chemokines, all of which may be produced by the melanoma tumor cells themselves. These studies suggest potential strategies to promote effector T cell migration to the tumor site that may include: direct introduction of chemokines; direct induction of chemokine production from stromal cells; eliciting local inflammation that generates chemokines (e.g., via type I IFNs, TLR agonists and possibly radiation); and altering signaling pathways in melanoma cells to enable chemokines expression by the tumor cells. Studies that have been designed to evaluate why melanomas that attract CD8+ T cells are not spontaneously rejected have pointed to several mechanisms that may exert negative regulation of T cells within the tumor microenvironment, including T cell inhibition via IDO and PD-L1, extrinsic suppression via CD4+CD25+FoxP3+ Tregs, and T cell anergy due to deficiency of B7 costimulation in the tumor microenvironment. Dr. Gajewski presented data that indicate that the immune inhibitory mechanisms present in the melanoma tumor microenvironment are driven by the CD8+ T cells, not the tumor. For example, IFNγ is the major mediator for IDO and PD-L1; and CCL22 production by CD8+ T cells is the major mediator for Tregs. Thus, blockade of these mechanisms may represent attractive strategies to restore anti-tumor T cell function and promote tumor rejection in patients.
To address questions underlying the mechanisms that promote spontaneous T cell priming in a subset of melanoma patients, Dr. Gajewski and colleagues used gene array data to identify markers of innate immunity that correlated with T cell infiltration. Melanoma metastases that contained T cell transcripts also contained transcripts known to be induced by type I IFNs. A knock-out mouse model demonstrated the necessity of the type I IFN axis for effective priming of a spontaneous T cell response and tumor rejection. Additional studies in knock-out mice have demonstrated that the CD8α+ DC subset is responsible for this spontaneous T cell priming. In an effective anti-tumor response sensing of the tumor by a separate DC subset drives type I IFN production, which is required for CD8α+ DC cross-priming of T cells. This suggests additional pathways that could be altered to promote spontaneous priming and an effective tumor response (e.g., provision of exogenous IFNβ). In summary, there is heterogeneity in patient outcomes to cancer immunotherapies (e.g., melanoma vaccines). One component of that heterogeneity is derived from differences at the level of the tumor microenvironment. Key factors in the melanoma microenvironment include
chemokine-mediated recruitment of effector CD8+ T cells, local immune suppressive mechanisms, and type I IFNs/innate immunity. Understanding these aspects should improve patient selection for treatment with immunotherapies (predictive biomarker), as well as aid the development of new interventions to modify the microenvironment to better support T cell-mediated rejection of tumors.

Source: http://www.translational-medicine.com/content/pdf/1479-5876-9-18.pdf

Induction of an immune response by antigen vaccination. Active immunization occurs following administration of tumor antigens, which are processed by antigen-presenting cells resulting in activation of immune effector cells such as T lymphocytes and B lymphocytes. Effector cells fight the tumor through several different effector pathways such as antibodies, cytokines or direct cellular interaction (Fas/Fas ligand, perforin/granzymes). Ideally this results in immunologic memory with long-lasting immunity against the tumor. Stimulation of the innate immune system is also known to have an important role in the evolution of an adaptive immune response (e.g. a rapid burst of inflammatory cytokines leads to activation of DC and macrophages). However, tumor-specific T cells also secrete chemokines (e.g. RANTES, MIP-1) that attract cells of the innate immune system to the tumor site. This mechanism may further contribute to the tumoricidal activitiy exhibited during T cell-mediated tumor regression. (TCR: T cell receptor, MHC: major histocompatibility complex, DC: dendritic cell, PMN: polymorphonuclear neutrophil, NK: natural killer cell, NKT: NK T cell, RANTES: regulated upon activation, normal T cell expressed, and secreted, (MIP-1): macrophage inflammatory protein 1)

Two companies that are pursuing Cytokine Therapies with a product of “Natural Mixtures of Cytokines.” They may provide the missing signal needed to raise the red flag, “The Danger Signal”

Multikine is in the Phase 3 and IRX-2 is in the Phase 1 clinical trial Phase
IRX Therapeutics seems to have the most appropriate mixture. Cel-SCI is missing the chemoattractants and proinflammatory cytokines.

If you combine the Cytokine therapy with anti-CTLA-4 blockage, will you get a synergistic immune response?

“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”
~Charles Darwin~
Take Care,
Jimmy B

Expanded access With RO5185426 in Patients With Metastatic Melanoma..Jim Breitfeller

2011-01-31T07:55:00.002-05:00
Expanded access With RO5185426 in Patients With Metastatic Melanoma.
The locations are limited.

The drug is called RO5185426, which is interchangeable with PLX4032 and RG7204. Also, you must be Braf positive and failed a prior therapy.

Expanded access With RO5185426 in Patients With Metastatic Melanoma

“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”

~Charles Darwin~
Take Care,
Jimmy B

CEL-SCI on cusp of cancer game-changer Melanoma..Jim Breitfeller

2011-01-29T21:45:00.000-05:00
This Cytokine Therapy may be helpful prior to Anti-CTLA-4 Blockade (Ipilimumab)or after. It may help send the Danger signal to involke the immune response.

CEL-SCI on cusp of cancer game-changer

“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”

~Charles Darwin~
Take Care,
Jimmy B

MSKCC to Test Agenus' Personalized Cancer Vaccine in Combination With Novel Immunomodulatory Agents Melanoma..Jim Breitfeller

2011-01-24T10:52:00.001-05:00
MSKCC to Test Agenus' Personalized Cancer Vaccine in Combination With Novel Immunomodulatory Agents

LEXINGTON, Mass., Jan. 24, 2011 (GLOBE NEWSWIRE) -- Agenus Inc. (Nasdaq:AGEN) today announced it has entered into a research agreement with Memorial Sloan-Kettering Cancer Center (MSKCC) using Agenus' proprietary cancer vaccine technology.

The collaboration will test Agenus' cancer vaccine in combination with antibodies that are intended to target specific markers on tumor cells, such as CTLA-4 and PDL-1. This group of antibodies represents a new class of immunotherapeutic agents that are thought to have complementary mechanisms of action with cancer vaccines. The studies will be performed in the laboratory of Jedd D. Wolchok, M.D., Ph.D., a leader in the field of cancer immunotherapy. Dr. Wolchok serves as the Associate Director of the Ludwig Center for Cancer Immunotherapy at MSKCC as well as Director of Immunotherapy Clinical Trials.

"Collaborating with MSKCC and Dr. Wolchok's laboratory opens a new chapter in the development of our personalized cancer vaccine portfolio for targeting later stages of this disease," said Garo Armen, Ph.D., CEO of Agenus. "Partnerships with leading institutions are central to Agenus' strategy to bringing life-changing products for cancer patients to market faster."

Agenus' cancer vaccine is designed to expand and specifically program the army of T-cells responsible for killing tumor cells; however, as cancer grows it becomes smarter and increasingly builds an 'immune fortress' that can protect itself from the attack of T-cells. Therefore, combining a product that activates T-cells with an agent that blocks the signal preventing the T-cells from effectively killing the tumor could have highly potent outcomes.

"Combination immunotherapy in cancer is increasingly becoming a key focus of research, and this collaboration will add to this important and growing knowledge base," said Dr. Wolchok. "Our interest in Agenus' cancer vaccine is that it contains many antigens that are genetically matched with the cancer as the product is derived from the tumor itself."

"In addition to this preclinical research effort, we are looking forward to opportunities to rapidly initiate clinical trials, combining our Prophage series of cancer vaccines with either marketed or investigational agents that work against T-cell down regulation," said Dr. Armen.

Source:Personalized Cancer Vaccine in Combination With Novel Immunomodulatory Agents

Combinatorial therapy will lead us toward a cure. Mark my words.

“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”
~Charles Darwin~
Take Care,
Jimmy B

Gene Therapy Eliminates Brain Tumors Through Selective Recruitment Of Immune Cells..Melanoma Jim Breitfeller

2011-01-15T12:08:00.003-05:00
Gene Therapy Eliminates Brain Tumors Through Selective Recruitment Of Immune Cells

http://www.sciencedaily.com/releases/2009/01/090112212447.htm

“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”
~Charles Darwin~
Take Care,
Jimmy B

Alarmins Initiate Host Defense against Melanoma, Let the war games begin..Melanoma ..Jim Breitfeller

2011-01-13T13:00:00.011-05:00
The immune system has evolved to respond not only to pathogens, but also to signals released from dying cells. These signals are generated by molecules call Alarmins.
In response to infection and/or tissue injury, cells of the host innate immune system rapidly produce a variety of structurally distinct mediators that not only function as potent effectors of innate defense but also act to alarm the immune system by promoting the recruitment and activation of host leukocytes through interaction with distinct receptors. One of these Alarmins is the High mobility group box 1 (HMGB1).

(HMGB1) is a DNA-binding nuclear protein, released actively following cytokine stimulation as well as passively during cell death; it is the prototypic damage-associated molecular pattern (DAMP) molecule and has been implicated in several inflammatory disorders, but our case, it is the molecule that sends the red flag up to the immune system, stating there is a problem.

This Alarmin (HMGB1) is capable of activating antigen-presenting cells (APCs) and enhancing the development of antigen-specific immune responses.

The interaction of high mobility group box 1 protein (HMGB1) released from dying tumor cells with Toll-like receptor 4 (TLR) on dendritic cell was required for the crosspresentation of tumor antigens and the promotion of tumor specific cytotoxic T-cell responses.

Under stress conditions, such as injury or infection, HMGB1 is released and promotes inflammation. (Danger Signal) HMGB1 is passively released by Death of cells or tissues through injury or disease (necrotic) but not apoptotic death. Disintegration of cells into membrane-bound particles that are then eliminated by phagocytosis or by shedding of normal cells and actively secreted by a variety of activated immune and non-immune cells.
Through the TLR4, HMGB1 activates NFκB inducing a wide range of host changes that include activation of the innate immune system (neutrophils, NK cells, dendritic cells) and secretion of proinflammatory cytokines and mediators.

There is growing evidence that the relationship between the inflammatory process and cancer is complex. Our understanding of this relationship as it relates to Danger Signal development and or progression of malignancy is still limited. Further evaluation in patients is clearly needed if we are to truly understand whether there is therapeutic potential in targeting Pro-inflammation, “The Danger Signal”.

HMGB1 as a DAMP released into the tumor microenvironment plays a central role in the recruitment and activation of innate immune cells.

This emergent understanding of the danger signals also called alarmins or damage associated molecular patterns (DAMPs) is fueling new research that may be beneficial to finding a cure.

This ability of dendritic cells to recreate the environment associated with necrosis via the regulated secretion of HMGB1 represents a successful evolutionary strategy and places HMGB1 at the crossroads between innate and adaptive immunity.

Once T-cells are activated, RAGE and HMGB1 are upregulated during cellular activation, consistent with a role of the RAGE axis in pro-inflammatory immune responses.

So how do we cause tumor cells to die? We don’t need to kill them all at once, that would be nice, and we need to a portion so that HMGB1 is secreted. Or do we inject a mixture of naturally occurring Cytokines that act as the pro-inflammatory cytokines, (the Danger Signal)?

.
A little known company is just doing that. The company is IRX Therapeutics.

Irx Therapeutics, Inc
2350 Broadhollow Road
Farmingdale, NY 11735-1006

Dr. John W Hadden founded the company in 1994 and holds the patent on the cytokine mixture called IRX-2.

The cytokine components of IRX-2 (includes IL-1, IL-2, IL-6, IL-8, IFN-γ, TNF-α, G-CSF and GM-CSF) are known to promote both T lymphocyte and dendritic cell development and function and monocyte function.

I believe the natural cytokine mixture (NCM). The NCM includes 1L1, IL2, IL6, IL8, IL10, IL12, .delta.IFN, TNF.alpha. and G- and GM-CSF could play a pivotal role in activation of the T-cells (CD4+ and CD8+). This mixture that is in the patent (20030206885) is what I would call the Proinflammatory Cytokines, the “Danger Signal”.

The natural cytokine mixture is missing MCP-1, MIP-1 alpha and beta which is very important to attract immune cells to the tumor’s microenvironment.

CCL3/MIP-1 alpha acts as a chemoattractant to a variety of cells including monocytes, T cells, Dendritic cells, B cells and eosinophils

CCL4/MIP-1 beta is expressed primarily by T cells, B cells, and monocytes after antigen or mitogen stimulation. The functional receptor for MIP-1 beta has been identified as CCR5.

CCL4, also known as macrophage inflammatory protein 1 beta (MIP1β)
is a 7.8 kDa β chemokine that is secreted at sites of inflammation by activated leukocytes, lymphocytes, vascular endothelial cells.

CCL4 attracts a variety of immune cells to sites of microbial infection as well as to other pathologic inflammation.

Monocyte chemoattractant protein-1 (MCP-1) is important in attracting monocytes to sites of inflammation. Besides induction of monocyte recruitment, MCP-1 can also affect chemotactic response of endothelial cells.

I speculate by combining Radiation, Chemotherapy, Ipilimumab, IRX-2, and IL-2 in a systematic way, we can induce an immune response against Melanoma and win most of the Battles. Let the war games begin. Who will take on this challenge and be the first to CURE Melanoma? We shall see.

A clue: This is from a patient that is receiving Ipilimumab (Yervoy)

“The Dr. says it's possible the swelling is caused by the tumors starting to respond. My back and leg tumors did become inflamed before they receded, so it's possible the same is happening in the brain. I could also be having a delayed reaction.”

From a paper of Dr. Meenhard Herlyn.

Inflammation is the key to the Danger Signal which can be produced by dying Tumor cells or Ipilimumab differentiating T-cells into Th-17 Phenotype or by injecting a pro-flammatory cytokine mixture. Let the War on Melanoma Begin!!!!!

“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”

~Charles Darwin~
Take Care,
Jimmy B

BMS denies any wrongdoing. Is this what we have to look forward to with Yervoy (Ipililumab) Melanoma..Jim Breitfeller

2011-01-06T08:53:00.005-05:00
Commentary:
BMS denies any wrong doing, but this was not it's first offence and may not be it's last. As the patent waterfall nears close with Plavix, is BMS trying to make up for it's loss of revenue?
Mesothelioma and Cancer Patients Who Received Certain Chemotherapy Drugs May be Eligible for Reimbursement

I am anticipating that BMS will try to inflat the cost of production of Ipilimumab (Yervoy) and try to pass it along to the patients that desperately need it. It is a shame that the drug companies have come down to greed and screw the consumer. BMS needs desperately to clean house again and go through some Ethics training, Big time!!!

I am all for paying a fair price, but not to get gouged to the point that the insurance won't pay and pass the copay onto the patients. It is not right.

Bristol Myer Slogan:

"What sets us apart? We believe it's our commitment to patients with serious diseases, our focus on finding innovative medicines that combat those diseases, and our dedication to extending and enhancing human life."

So we can deplete your life savings for the good of the company and line our pockets!!!!

“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”

~Charles Darwin~

Take Care,

Jimmy B

Oncologic Drugs Advisory Committee scheduled for February 9, 2011, is cancelled. Ipilimumab (Yervoy)

2011-01-05T13:59:00.001-05:00
Oncologic Drugs Advisory Committee scheduled for February 9, 2011, is cancelled. Ipilimumab (Yervoy)

Federal Register Volume 75, Number 247 (Monday, December 27, 2010)]
[Notices]
[Page 81283]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 2010-32413]

-----------------------------------------------------------------------

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2010-N-0001]

Oncologic Drugs Advisory Committee; Cancellation

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

-----------------------------------------------------------------------

SUMMARY: The meeting of the Oncologic Drugs Advisory Committee
scheduled for February 9, 2011, is cancelled. This meeting was
announced in the Federal Register of December 6, 2010 (75 FR 75680). On
February 9, 2011, the Oncologic Drugs Advisory Committee was scheduled
to discuss biologics license application (BLA) 125377, with the
proposed trade name YERVOY (ipilimumab), submitted by Bristol-Myers
Squibb Co. The proposed indication (use) for this product is for the
treatment of advanced melanoma in patients who have received prior
therapy. This meeting has been cancelled because the issues for which
FDA was seeking the scientific input of the committee have been
resolved.

FOR FURTHER INFORMATION CONTACT: Nicole Vesely, Center for Drug
Evaluation and Research, Food and Drug Administration, 10903 New
Hampshire Ave., Bldg. 31, rm. 2417, Silver Spring, MD 20993-0002, 301-
796-9001, FAX: 301-847-8533, e-mail: Nicole.vesely@fda.hhs.gov, or FDA
Advisory Committee Information Line, 1-800-741-8138 (301-443-0572 in
the Washington, DC area), and follow the prompts to the desired center
or product area. Please call the Information Line for up-to-date
information on this meeting.

Dated: December 21, 2010.
Jill Hartzler Warner,
Acting Associate Commissioner for Special Medical Programs.
[FR Doc. 2010-32413 Filed 12-23-10; 8:45 am]
BILLING CODE 4160-01-P

“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”

~Charles Darwin~

Take Care,
Jimmy B

Yervoy (ipilimumab) melanoma immune-based therapy at FDA Feb 9, 2011

2010-12-19T17:37:00.002-05:00
Yervoy (ipilimumab) melanoma immune-based therapy at FDA Feb 9, 2011

"Activatng the immune system is a relatively new model for attacking cancer, but it appears to be coming of age. While "true breakthrough" is a term rarely applied in most treatments, ipilimumab (proposed brand-Yervoy) may be just that for patients with melanoma."

Source:Yervoy (ipilimumab) melanoma immune-based therapy at FDA Feb 9, 2011

Yervoy, may become the new gold Standard in the fight against Melanoma. I hope Bristol-Meyer Squibb doesn't screw it up by overcharging for the Drug because there are many ways to jump start the immune system and Ipilimumab(Yervoy) is just one of them.

“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”

~Charles Darwin~
Take Care,
Jimmy B

Killing Drug-Resistant Melanoma Requires Combination Therapy

2010-12-15T17:59:00.003-05:00
Killing Drug-Resistant Melanoma Requires Combination Therapy

The researchers see this as further evidence that some cancers must be treated with multiple targeted drugs at the outset of treatment. Their findings are published in the December 14 issue of the journal Cancer Cell.

"The evidence suggests that targeting mutant BRAF can kill cancer cells, but it is not enough by itself to finish off melanoma," said Meenhard Herlyn, D.V.M., D.Sc., director of The Wistar Institute Melanoma Research Center and leader of Wistar's Molecular and Cellular Oncogenesis program. "The good news is that drugs are being developed to work in combination with BRAF inhibitors, which our data clearly shows is our best option if we intend to beat advanced melanoma."

Melanoma is the deadliest, most aggressive form of skin cancer. While surgical treatment of early melanoma leads to 90 percent cure rates, advanced melanoma is notoriously resistant to chemotherapy and has a tendency to metastasize, or spread, throughout the body. According to the World Health Organization, cases of the disease continue to rise, which has helped spur research into therapies such as BRAF inhibitors.

To study how melanoma responds to BRAF inhibitors, the Herlyn lab took melanoma cells with the BRAF mutation and tested them against a variety of anti-mutant BRAF drugs. When exposed to the drugs, the cells died off dramatically only to grow back again. In fact, cells that became resistant to one type of BRAF drug became resistant to all of them, which suggests that the cells were biochemically "rewired" in such a way that they no longer needed BRAF to form tumors.

"Cells are complex machines that work, essentially, through chains of biochemical reactions that we refer to as signaling pathways," said Jessie Villanueva, Ph.D., senior author on the study and staff scientist in the Herlyn laboratory.

"Knocking out mutant BRAF shuts a major pathway down, but if some cells can use an alternate pathway, then they can survive."

To find out which alternate pathways the drug-resistant cells use, Villanueva and her colleagues looked for signs of increased activation among proteins along the pathways BRAF uses, as well as other pathways.

Their hunt turned up two paths that worked together to aid survival. First, they found that resistant cells used a protein similar to BRAF to carry the signal down the chain. Second, they found these cells received an additional boost from the IGF-1 receptor, a protein that sits on the surface of cells and sends signals that prevent cells from being killed. The resistant cells re-route the signal around BRAF by switching to an alternate protein (CRAF or ARAF), which promotes tumor cell growth, while IGF-1R signaling promotes survival of the resistant cells.

Fortunately, there are a number compounds in clinical development that could block signals along both these pathways. So-called MEK inhibitors target a protein along the same pathway as BRAF, and IGF-1 receptor inhibitors (and inhibitors of P13K, a protein that can be activated by the IGF-1 receptor pathway) block the cancer-enabling survival signal. To test these drug combinations in the BRAF-inhibitor resistant cells, the Herlyn laboratory used a tool they developed to simulate the real-world environment of human cells: 3-D melanoma tumor spheroids. Their 3-D tissue cultures allow melanoma cells to grow in all directions, much like a new melanoma tumor would grow after metastasis. As predicted, a combination of these two inhibitors killed BRAF-resistant melanoma cells in the Wistar 3-D model.

Moreover, the Herlyn laboratory confirmed in tissue samples from patients in the PLX4032 trial -- taken both before treatment and after they developed resistance -- that an increased expression of the IGF-1 receptor is associated with resistance to BRAF inhibitors. None of the laboratory-generated cell lines or the post-relapse patient's tumor samples analyzed had new mutations in the BRAF, NRAS, or c-Kit genes.

Additionally, the researchers noted an association between the loss of a tumor suppressor called PTEN, and resistance to BRAF inhibitors in melanoma cell lines. The scientists found that the relapsed tumor of one patient included in the study lost the PTEN gene, even though it was present before treatment. These findings suggest that loss of PTEN could be an additional way that melanoma cells gain resistance to BRAF inhibitors. The Wistar group continues to investigate these and other mechanisms of resistance, as they expect that several will likely arise given the heterogeneous nature of melanoma.

"Tumors are efficient engines of evolution -- they are going to find a way around most treatments, so we want to kill all the malignant cells from the very beginning," said Villanueva. "By targeting both pathways simultaneously you hit these cells with two punches from which they cannot recover."

"If you do this at the outset of treatment, we reason, it will prevent melanoma survival and hopefully improve patient outcomes," Villanueva added.

Support for this study was provided by grants from the National Cancer Institute and the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation.

Wistar co-authors in this study include Adina Vultur, Ph.D.; John T. Lee, Ph.D.; Rajasekharan Somasundaram, Ph.D.; Mizuho Fukunaga-Kalabis, M.D., Ph.D.; Angela K. Cipolla; James E. Hayden; and Ademi E. Santiago-Walker, Ph.D. University of Pennsylvania School of Medicine co-authors include Katherine L. Nathanson, M.D.; Xiaowei Xu, M.D., Ph.D.; Phyllis A. Gimotty, Ph.D.; Bradley Wubbenhorst; Richard Letrero; Kurt D'Andrea; and Anitha Pushparajan. Other authors included Grant A. McArthur, M.B., B.S., Ph.D.; and Damien Kee, MBBS, FRACP, of the Peter MacCallum Cancer Centre in Victoria, Australia; Jeffrey A. Sosman, M.D., and Kimberly Dahlman Brown of the Vanderbilt University Medical Center; and Sylvie Laquerre, Ph.D., of GlaxoSmithKline's division of Oncology Biology in Collegeville, Pa.

Disclaimer: This article is not intended to provide medical advice, diagnosis or treatment. Views expressed here do not necessarily reflect those of ScienceDaily or its staff.

“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”

~Charles Darwin~
Take Care,
Jimmy B

Food and Drug Administration Has Extended the Review Timeline for the Ipilimumab Biologics License Application Melanoma..Jim Breitfeller

2010-11-02T18:34:00.004-04:00
FDA Has Pushed backed the Review Timeline for the Ipilimumab Biologics License Application to March 26, 2011. How many Melanoma Patients need to die before Ipi is FDA approved? Who do we blame, BMS or the FDA. Someone should be held accountable.

Food and Drug Administration Has Extended the Review Timeline for the Ipilimumab Biologics License Application

“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”
~Charles Darwin~
Take Care,
Jimmy B

The Accelerator..IL-2 Therapy..Melanoma Cancer..Jim Breitfeller

2010-10-28T09:41:00.003-04:00
The Food and Drug Administration this year approved a “cancer vaccine” for prostate cancer called Provenge, so-called because it trains the immune system to attack the patient’s tumors. Most such vaccines focus on a single type of cancer, or are even tailored to individual patients.

Ipilimumab, by contrast, is a more general immune booster. It blocks a protein called CTLA-4 that acts as a brake on T cells, the soldiers of the immune system. It is already also being tested against lung and prostate cancer.

Still, if a tumor does not elicit a strong immune response to begin with, then just keeping the response going longer would not help much, just as lifting one’s foot from the brake usually will not make a car go faster if the accelerator is not pressed. The accelerator needed is Interluekin-2 (IL-2.

IL-2 induces inflammation at tumor sites(Danger Signal) with three predominant secondary effects:

1)activation of antigen-presenting monocytes.

2) massive production of chemoattractants that may recruit other immune cells to the tumors.

3) activation of cytolytic mechanisms in monocytes (calgranulin, grancalcin) and NK cells NKG5, NK4.

The take away; systemic combinatorial therapy is one of the best ways to utilize the immune system to induce an immune response to Melanoma Cancer.

“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”
~Charles Darwin~

Take Care,

Jimmy B

Tumors shut down the Third Signal needed for T-cell Activation..Melanoma Cancer..Jim Breitfeller

2010-10-26T16:56:00.005-04:00
A picture is worth a thousand words.

STAT-3 signaling from the tumors blocks the pro-inflammatory cytokines, so no danger signal is sent to the immune system.

The Missing Link in T-cell activation using a Vaccine, "The Danger Signal"

DCs leads to enhanced induction of Th17-1 cells. These data demonstrate the capacity of DCs to induce expansion of polyfunctional IL17-producing T cells in humans, and suggest a role for DCs in the enrichment of Th17-1 cells in the tumor bed.

Tumor bed is heavily infiltrated by DCs, which, as shown here, are the most efficient inducers of human Th17 cells. The data supports a model in which Th17 cells are recruited to the tumor bed by Th17-attracting chemokines (eg, CCL20, recently shown to be enriched in the melanoma tumor bed) and activated to a Th17 phenotype locally by tumor-infiltrating DCs. The capacity of DCs to induce Th17 cells may be further enhanced by the uptake of apoptotic tumor cells, as well as inflammatory cytokines (eg, IL1, IL6, TNF) in the tumor bed. This gives rise to T-cell activation and the inflamed response leading to immune response.

For the tumor to survive the immunologic suppression system, it must turn on pathways (such as Stat3) that inhibit production or sensing of proinflammatory danger signals that activate innate and adaptive immune responses. Tumors that successfully accomplish this can shift the balance of immunity from activation to tolerance induction. Pardol et al But what if, the production of Proinflammatory cytokines can over come the suppressive function of the tumor’s microenvironment? Could the differentiation of the CD4+ T-cells into Th17 be the path to activation and immunity responses? If that is the case, then Anti-CTLA-4 blockade (ipilimumab) plays more of a major factor in adaptive immunity then we originally thought.

“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”
~Charles Darwin~
Take Care,
Jimmy B

The Future of Immunotherapy.. Emerging concepts in biomarker discovery.Melanoma.Jim Breitfeller

2010-10-25T11:19:00.003-04:00
Emerging concepts in biomarker discovery!!!!!2009

Take away: Get your blood and tumors profiled for Biomarkers. It could lead you to the right therapy to do.

A table of:
Emerging biomarkers potentially useful for the immunotherapy of cancer.

A Table of:
Emerging biomarkers potentially useful for the immunotherapy of cancer.

Source:Emerging concepts in biomarker discovery; The US-Japan workshop on immunological molecular markers in oncology

Dr. Kirkwood give his honest opinion on the clinical trails to date and where they are heading in the future incliding Biomarkers.

Please take an hour out of you day to view and listen, It may save you or your love one from doing the wrong therapy.

Dr. Kirkwood talks about autoimmunity through out the presentation
NIH Scientists Discover Secrets Of Helper T Cells Involved In
Autoimmunity.... Th17 cells!!!!!!

“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.

”~Charles Darwin~

Take Care,
Jimmy B

Questions and Answers from Jim In Denver Co..Melanoma..Jim Breitfeller

2010-10-22T10:00:00.008-04:00
Jim,
First of all thank you for replying to my post. I usually don’t get many replies. When I talk to my wife about this, within the first five minutes she is telling me “I am loosing her.” It has taken me close to three years to get to where my knowledge on melanoma and the immune system is today. I don’t mean to talk over patient heads. It is just the scientist in me. I worked at Eastman Kodak’s Research laboratories for 25 years.

Now to answer you first question:

You have said that the most effective durable treatment for advanced melanoma would consist of Ipilimumab combined with IL2 - is that correct?

Based on my research today, IL-2 and Anti-CTLA-4 (Ipilimumab) are most durable as we speak. A new phase I therapy is showing great promise with less side effects. That is anti-PD-1 Therapy. These therapies don’t need a specific HLA type to get into the trials.

There is also a very, very ,very new therapy that is still in translational stage. Translational research is a way of thinking about and conducting scientific research to make the results of research applicable to the population under study and is practised in the natural and biological, behavioural, and social sciences. It is usally conduted with animals like rats, mice, monkeys.

Anyway this therapy combines the Anti-CTLA-4 and Anti-PD-1. It has shown synergistic results.

If you have c-Kit or BRAF mutations, then targeted therapy may used but may not be durable.

If you are HLA-02 Positive, You have the option of ACT therapy with Dr. Rosenberg or Dr. Patrick Hwu at NCI or MD Anderson. They have gotten 72 % response rate with I think about 36 % complete response is I am not mistaken.

Second Question:
There are no studies currently availble that combine Ipi and IL2, is that correct?
Define combine? There was a clinical study done by Dr. Rosenberg and colleages.

As you can see in the graph above, IL-2 was added prior to the maximum propagation of the CD4+ T helper cells. IL-2 is known as a growth factor. So what I believe happened in this trial, they grew the Tregs.

IL-2 treatment during the expansion phase was detrimental to the survival of rapidly dividing effector T cells. In contrast, IL-2 therapy was highly beneficial during the death phase, resulting in increased proliferation and survival of Tumor-specific T cells. IL-2 treatment also increased proliferation of resting memory T cells in the host that controlled the disease. A tumor-specific T cell in chronically infected Host also responds to IL-2 resulting in decreased tumor burden. Thus, timing of IL-2 administration and differentiation status of the T cell are critical parameters in designing IL-2 therapies (Blattman et al., 2003).

So what I am trying to say is you do the Ipilimumab therapy first. Wash out for about 50 days, and then start IL-2 Therapy.

Take away: It is a systemic combination with dosing and timing involved. Systemic Combinatorial Therapy.

Question 3:

If someone were to choose to do a combination treatment on their own (i.e. get IL2 following a course of Ipi through one of the clinical trials), would there be an advantage
to starting IL2 as soon as possible after stopping Ipi? Is there a time frame after which there would be no advantage to having received Ipi prior to taking IL2?

Base on papers from ITOH etal and others, 49 days after activation is at the maximum growth phase for the CD8- T-cells that mature into Cytotic T Lymphocytes.

Results: Graph setup

Kinetic Study of rIL-2-induced Expansion. In all 12 metastatic melanomas tested, a substantial proportion of TIL was present in tumor cell suspensions.
The ratio of lymphocytes to tumor cells ranged from 0.03 to 1.25 with an average ratio of 0.40 t 0.37. By fluorescence analysis,
TIL consisted of 78 days 11% CD3
T cells, 33 days 10% CD4+
T cells, 49 days 17% CD8+
Their CD4/CD8 ratio was 0.67.
(ITOH et al., 1988)

It was also reported that there is a time factor involved.
Our results show that T4 + human T cells differ substantially from T8 + cells with respect to their IL-2 responsiveness. T4 + cells cease to proliferate well before T8 + cells during a primary response. (GULLBERG AND SMITH et al.,1986)

Is there a time frame after which there would be no advantage to having received Ipi prior to taking IL2?

Yes, Ipilimumab has a half life of 15 days. So say you get one dose at 3.0 mg/Kg.

Days-- concentration
0-- 3
15-- 1.5
30-- 0.75
45-- 0.375
60-- 0.1875
75-- 0.09375
90-- 0.04687
105-- 0.02343
120-- 0.01171
135-- 0.00587
150-- 0.00292
165-- 0.00146
180-- 0.00073

It gets more complicated when you get multiple doses. Four dose regiment.

Days-- concentration
0-- 3
15-- 1.5
30-- 3.7
45-- 4.85
60-- 5.425
75-- 2.7125
90-- 1.35625
105-- 0.68
120-- 0.34
135-- 0.17
150-- 0.08
165-- 0.04
180-- 0.021

I am not sure where the limited threshold is but, at day 49 you have close to the maximum concentration of Ipilimumab in your body.

Since I used Tremelimumab with Half Life = 21 days and did 15mg/Kg

I had at day 50 approximately 2.17 mg/Kg anti-CTLA-4 level in my body

If I had to venture an educational guess, I would say after a four dose regime, you have 75 days to do the HD IL-2.

To back this theory up, we will use a chart from Dr. Wolchok experience the Ipilimumab.

It is a chart with the Absolute Lymphocyte count. (ALC). It is the CD4+ T-cells and CD8+ T cells combined.

As you can see from the graph, the maximum ALC was about week 7.
Week seven correlates to 49 days. That is when CD8+ T cells are at their maximum growth.

Question 4:

Last, is there any evidence that IL2's efficacy is enhanced by combining it with other agents (i.e. Biochemotherapy), either with or without first receiving Ipi?

This my take on the situation. You need the tumor-specific antigen to presented to the T-cells as signal 1. That could be a vaccine, radiation therapy or chemo to shed the antigen.
Secondly you need the costimulation of the CD28/B7 interface. By using Ipilimumab that blocks the CTLA-4 receptor from binding to the B7 molecule and shutting down the response.
Anti-CTLA-4 (ipilimumab) also blocks the CTLA-4 receptor on the Treg cells subduing their surpress function.

Third you need a “Danger Signal” to get the cell to migrate to the tumor site. This may be done with inflammatory Cytokines like IL2, IL17, IL-1,IL-12,IFN gamma that act directly on the T-cells. This signal was found to optimally activate the Th1 differentiation and lead to the clonal expansion of the T-cells.
It has come to light recently that Ipilimumab helps also in the differentiation by tilting the balance towards Th17 cells. These cells secrete IL-17 which recruite the neutrophils. This all takes place at the tumor’s microenviroment. The neutrophils secrete chemokines that are chemoattractants.

These chemokines, MIP-1alpha, MIP-1beta, and MCP-1 are recently reported to serve as chemoattractants for Th1 cells. MIP-1alpha and MCP-1 are also reported to enhance antigen-specific (CTL) Cytotoxic T Lymphocyte induction. Studies revealed that MIP-1alpha /beta released from neutrophils are involved in recruitment of macrophages, T cells, monocytes, dendritic cells (DC), neutrophils and NK cells.
MIP-1 attracts predominantly CD8+ T cells while MIP-1 attracts CD4+ cells, although there is some overlap between subsets in response to both chemokines.
The other Chemokine MCP-1, binds to CCR2 to accumulate monocytes/macrophages, DC, T cells, and NK cells, thereby playing an important role in innate and adaptive immunity. CCR2 is Chemokine receptor that is key determinant of leucocyte trafficking.

IL-2 strongly upregulates expression of CCR2. With the MCP-1/CCR2 interface, the cells can traffic towards the tumor’s microenvironment. The trafficking of the cells and inflammatory cytokines present the perfect storm in the tumor’s microenvironment to induce the right immune response to eradicate the cancer, Melanoma.
So to answer your question, is there any evidence that IL2's efficacy is enhanced by combining it with other agents (i.e. Biochemotherapy), either with or without first receiving Ipi? yes if you know and take a systemic approach. You need to activate the t-cells before introducing IL-2. IL-2 can be the activator for small patient population.

As for Ipilimumab going it alone, like IL-2 can be the activator for small patient population. But when you do a systematic combinatorial therapy, there can be a synergetic result, complete response.
I hope I answered you questions, and please don’t hesitate to ask them. I do all this time by requesting reseach papers from around the world. Each question is a learning tool. There are no stupid questions. Knowledge is power to make an educated decision. Your Life may depend on it. There are many paths to take. Just follow the yellow brick road to complete response.

“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”

~Charles Darwin~
Take Care,
Jimmy B

NIH Scientists Discover Secrets Of Helper T Cells Involved In Autoimmunity..Melanoma..Jim Breitfeller

2010-10-21T10:48:00.004-04:00
NIH Scientists Discover Secrets Of Helper T Cells Involved In Autoimmunity
October 21, 2010

A race for a cure!!!!!!! Let the games begin!!!!!

WHATScientists at the National Institutes of Health have redefined the roles of several cytokines involved in the generation of immune cells implicated in severe autoimmune diseases. The study in mice showed that development of Th17 immune cells can occur without the presence of transforming growth factor (TGF)-beta, a mediator thought to be required for Th17 cell development. The study demonstrates that the interaction of three inflammatory cytokines (proteins that influence the behavior of cells) - interleukin-6 (IL-6), IL-1-beta and IL-23 - is responsible for the creation of Th17 cells that are more active in promoting autoimmunity than Th17 cells generated with IL-6, IL-1-beta and TGF-beta. These findings reemphasize the separate roles of IL-23 and TGF-beta in immunity and autoimmunity, and open up possibilities for the development of new therapies. The study appears in the current issue of the journal Nature.

The immune systems of mice and humans mainly consist of B cells and T cells. While B cells fight infections and can induce autoimmunity by producing antibodies that directly target foreign antigens or a person's own tissue, T cells are involved in overall cell-mediated immunity. Importantly, how a T helper (Th) cell differentiates (develops from an immature, unspecialized cell into a mature, specialized cell) determines how it mediates immune responses. Th17 cells produce IL-17, a powerful inflammatory cytokine, and have been implicated in multiple autoimmune diseases, including rheumatoid arthritis, psoriasis and multiple sclerosis. The established belief has been that Th17 cells initially differentiate in response to activation by IL-6 and TGF-beta. However, previous research has shown that TGF-beta is primarily associated with suppressing immune functions and promoting regulatory T cells (Treg), which can produce inhibitory cytokines that dampen inflammatory immune responses.

In the present study, the NIH scientists first looked at the conditions to differentiate Th17 cells from naïve T cells outside of the mouse (in vitro) and tried several different cocktails of cytokines to see which combinations would promote Th17 development. They found two combinations that efficiently induced Th17 differentiation. As previously described, IL-6, IL-1-beta, and TGF-beta-1 together created Th17 cells. Surprisingly, IL-6, IL-1-beta, and IL-23 without TGF-beta also created Th17 cells. Most interestingly, the action of Th17 cells generated with IL-23, designated Th17(23), was different from the action of Th17 cells generated with TGF-beta (Th17(beta)). The researchers compared transcription factors, receptors and mediators of the two Th17 subtypes and looked at the pathogenic activity of both Th17 subtypes in mice during experimental autoimmune encephalomyelitis (EAE), a common model of autoimmunity that mimics some aspects of multiple sclerosis. They found that Th17(23) cells provoked significantly more severe disease than did Th17(beta) cells.

These findings suggest a new model for Th17 generation and the existence of functionally different subtypes of Th17 cells. This study also provides a better understanding of the array of immune components involved in autoimmunity and suggests possibilities for new targeted therapies.

NIH scientists contributing to this study are affiliated with the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), the National Institute of Dental and Craniofacial Research (NIDCR), and the National Institute of Allergy and Infectious Diseases (NIAID). Additional support was provided by Merck Research Laboratories (Schering-Plough Biopharma), Palo Alto, Calif.

REFERENCE
Ghoreschi K, Laurence A, Yang XP, Tato CM, McGeachy MJ, Konkel J, Ramos HL, Wei L, Davidson T, Bouladoux N, Grainger J, Chen Q, Kanno Y, Watford WT, Sun HW, Eberl G, Shevach E, Belkaid Y, Cua DJ, Chen W, O'Shea JJ. Enhanced Pathogenicity of Th17 cells Generated in the Absence of Transforming Growth Factor-ß Signaling. Nature. 2010 October 21;467(7318): 967-971.

WHO
John J. O'Shea, M.D. Scientific Director, National Institute of Arthritis and Musculoskeletal and Skin Diseases, is available to comment on this article.

CONTACT
To schedule interviews, please contact Trish Reynolds, 301-496-8190, .

About National Institute of Arthritis and Musculoskeletal and Skin Diseases
The mission of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), a part of the Department of Health and Human Services' National Institutes of Health (NIH), is to support research into the causes, treatment, and prevention of arthritis and musculoskeletal and skin diseases; the training of basic and clinical scientists to carry out this research; and the dissemination of information on research progress in these diseases. For more information, visit http://www.niams.nih.gov.

About The National Institute of Dental and Craniofacial Research
The National Institute of Dental and Craniofacial Research (NIDCR) is the Nation's leading funder of research on oral, dental, and craniofacial health. For more information, visit http://www.nidcr.nih.gov/.

About National Institute of Allergy and Infectious Diseases
The National Institute of Allergy and Infectious Diseases (NIAID) conducts and supports research -- at NIH, throughout the United States, and worldwide -- to study the causes of infectious and immune-mediated diseases, and to develop better means of preventing, diagnosing and treating these illnesses. For more information, visit http://www.niaid.nih.gov.

About National Institutes of Health
The National Institutes of Health (NIH) -- The Nation's Medical Research Agency -- includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases. For more information, visit www.nih.gov.

SOURCE: National Institutes of Health

NIH Scientists Discover Secrets Of Helper T Cells Involved In Autoimmunity
October 21, 2010

“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”
~Charles Darwin~
Take Care,

Jimmy B

Dilated capillaries at the melanoma tumor’s microenvironment caused by inflammation cytokines is the beginning of the “Danger Signals”.Jim Breitfeller

2010-10-19T23:34:00.016-04:00

Three major events must occur to induce CD8+ T cell–mediated, tumor-protective immunity against melanoma.

First, the T-cell receptor must be triggered by a (or multiple) self antigen–derived peptide MHC class I complex. Therefore, this event depends entirely on appropriate antigen presentation, which is most efficiently provided by mature dendritic cells. Peripherally tolerant or “ignorant” self-reactive T-cell clones, once properly activated, may serve as tumor-specific effector T cells.

Second, simultaneously with T-cell receptor triggering, a distinct second costimulatory signal must be delivered, mediated by IL-2, B7-1, or B7-2, which engage IL-2 receptors and CD28 on the surface of the T cell, respectively (17). A source of these cofactors for effective CD8+ T-cell stimulation can be provided by CD4+ T cells that release critical amounts of IL-2, or by mature dendritic cells that display an increased level of B7-1/B7-2 costimulatory molecules on their cell surfaces.

Third, inflammatory cytokines, including IL-1, IL-6, IL-12, and IFN-γ provide a third signal that acts directly on T cells, referred to as the “danger signal”. This signal was found to optimally activate TH1 differentiation and lead to clonal expansion of T cells.1

The inflammatory cytokines act to promote T cell responses. They include IL-1, IL-6, IL-12, TNF-α, and IFN-g produced by macrophages and/or dendritic cells. Th17 cells also plays a part by secreting IL-17 and others. The most notable role of IL-17 is it involvement in inducing and mediating proinflammatory responses. Neutrophils are the earliest cells to arrive at the inflammatory site.

While TGF-β is a critical differentiation factor for Treg cells, IL6 completely inhibits the generation of Treg cells induced by TGF-β. Instead, IL6 and TGF-β together induce the differentiation of pathogenic Th17 cells. With IL-6 missing in the microenvironment, Treg Cells flourish.

If the CD4 + T cells differentiate into TH2 cells that produce IL-4, the other cells inhibited to produce IL-6. IL-4 was found to inhibit TNF-α and IL-1β by activated monocytes almost 100 %. The Secretion of IL-6 was decreased by approximatly 80 % in the presences of IL-4 Cytokine. TE Velde et al 1990

Neutrophil recruitment can also be induced by cytokines such as IL-17 and Tumor necrosis factor (TNF). Among the family of IL-17 cytokines, IL-17A and IL-17F are able
to promote the recruitment of monocytes and neutrophils via the induction of other cytokines and chemokines such as G-CSF and IL-8 by various cell types.

IL-17 appears to be involved in promoting neutrophil influx into the tumor site. With the influx of neutrophils in the tumor’s microenvironment and the inflammatory cytokines, capillaries at the melanoma tumor’s microenvironment become dilated, making room for the recruitment of immune cells.

Neutrophils also play an important role in promoting or suppressing the Th1 immune response, which is mediated partly by induction of cytokines or chemokines. Depending on the compositional makeup of the microenvironment, the neutrophils can promote the right immune response. Studies revealed that these neutrophils secreted three different chemokines. Some of these chemokines are known as chemoattractants. A chemoattractant is a chemical (chemotactic) agent that induces an organism or a cell, a leukocyte, to migrate toward.

These chemokines, MIP-1alpha, MIP-1beta, and MCP-1 are recently reported to serve as chemoattractants for Th1 cells. MIP-1alpha and MCP-1 are also reported to enhance antigen-specific (CTL) Cytotoxic T Lymphocyte induction. Studies revealed that MIP-1alpha /beta released from neutrophils are involved in recruitment of macrophages, T cells, monocytes, dendritic cells (DC), neutrophils and NK cells.
MIP-1 attracts predominantly CD8+ T cells while MIP-1 attracts CD4+ cells, although there is some overlap between subsets in response to both chemokines.

The other Chemokine MCP-1, binds to CCR2 to accumulate monocytes/macrophages, DC, T cells, and NK cells, thereby playing an important role in innate and adaptive immunity. CCR2 is Chemokine receptor that is key determinant of leucocyte trafficking.
IL-2 strongly upregulates expression of CCR2. With the MCP-1/CCR2 interface, the cells can traffic towards the tumor’s microenvironment. The trafficking of the cells and inflammatory cytokines present the perfect storm in the tumor’s microenvironment to induce the right immune response to eradicate the cancer, Melanoma.

Neutrophils circulate in the bloodstream and must be signaled to leave the bloodstream and enter tissues. The signal often comes from the bacteria themselves, from complement proteins, or from damaged tissue, all of which produce substances that attract neutrophils to a trouble spot. (The process of attracting cells is called chemotaxis.)

The combination of chemoattractants and inflammatory cytokines, in the tumor’s microenvironment, helps to send out a Danger Signal which in turn invokes the right immune response to eradicate the Melanoma tumors.

“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”
~Charles Darwin~

Take Care,

Jimmy B

It takes two (IL-2) to Tango! Melanoma..Jim Breitfeller

2010-10-15T16:08:00.013-04:00

Immune responses involve multiple cell-cell interactions within lymphoid tissues, the
trafficking of activated cells to sites of effector function, and the migration of such effector cells within peripheral tissues. To gain a more detailed appreciation of the dynamics of such cell behavior and the relationship between cell dynamics and function, I have put together a series of events that take place during the activation phase of the immune response.

We know based on research that once the CD4+ T cell is activated, within two hours the IL-2 expression and IL-2 receptor are unregulated. IL-2 is secreted 45 minutes into this activation phase.

Experimental work has shown that IL-2 signaling in the first 10 hours is critical for the proliferation decision of T cells in culture. The spacial resolution of the Tregs and the T helper cells during this phase plays a major part in the immune response.
Secreted IL-2 is competed for by the Tregs and the activated CD4+ and CD8+ T-cells. If the Tregs are in close proximity of the T effector cells that are secreting the IL-2, the Tregs will create an IL-2 sink in the microenvironment. This will cause the proliferation and survival of the Tregs which suppresses the effector cell function. The IL-2 sink is where all the IL-2 that is secreted by the T helper cells is adsorbed by the IL-2 receptors on the Treg cells. Tregs don’t have the capability to produce IL-2 so they must scavenge the IL-2 out of the microenvironment of the CD4+ T helper cells. In Treg cells, the IL-2 gene is silenced and IL-2Rα is constitutively expressed through the action of the Treg-lineage-specifying transcription factor FoxP3.

The model proposed by Dr. Dorothea Busse and colleages predicts that the IL-2 secretion rate must exceed a threshold value Theta (θ) to switch IL-2Rα expression to the activated state and permit extensive autocrine IL-2 signaling.

This is just like the three little bears. You need the microenviroment conditions just right to activate T Helper cells.

As you can see in the above diagram, you don’t need high concentration of IL-2, you need spacial distance from one cell to the other. That can be achieved by Anti-CTLA-4 Blockage. By blocking the CTLA-4 receptors, the spacial distance between the T helper cell and the Treg cells increases and it also helps to differentiate the niave CD4+ T cells into Th17 cells.

IL-2 is mainly captured by the Treg cell, whereas autocrine reuptake by the T helper cells predominates when the cells are further apart. So we want to introduce IL-2 before the tumor recruites the Tregs to the Tumor Microenviroment and or when the Treg population is in the contration phase of the CD4+ T-cell cycle.

Cellular signal response is potentially controlled by ratio between ligand (IL-2)
number and surface receptor (IL-2R) number per cell.

Ligand n. An ion, a molecule, or a molecular group that binds to another chemical entity to form a larger complex.
.

Suboptimal amounts of IL-2 during priming promoted apoptosis, little proliferation and cell cycling, yet the CD8+ effectors generated produced high levels of cytokines and proliferated autonomously. Although IL-2 deprivation caused apoptosis and little proliferation initially, the effectors generated under these conditions possessed optimal effector functions. This low IL-2 concentration, allows the T help cell to activate and proliferate.
This is the reason why it takes a while for the tumors to begin to shrink because of little proliferation at first. It takes time for the immune system to assemble an army of Cytotoxic T Lymphocytes.

So how can we minimize the proliferation of the Tregs which are a subset of CD4+ T-cell subset without doing a full blown depletion of the CD4+ T-cells?

1. Anti-CTLA-4 Blockage
2. Local IL-21 Promotes the Therapeutic Activity of Effector T cells by
Decreasing Regulatory T Cells Within the Tumor Microenvironment
3. Anti-PD-1 Blockage
4. A combination of the above three.

This is the future of Melanoma Therapy, Combinatorial Therapy.

“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”
~Charles Darwin~

Take Care,
Jimmy B

ASCO 2010 Long Term Survival Benefit in Melanoma...Jim Breitfeller

2010-10-12T08:47:00.005-04:00

As you can see the combinatorial therapy of Anti-CTLA-4 and Interluekin-2 give the best complete response. I am convince that if they adjust the timing and dose, they will see an even higher response rate in overall survival.

The Making of an Immune Response by Combinatorial Therapy Using Anti-CTLA-4 Blockade and Interleukin-2

The paper that I am about to present to you is a culmination of research that was done base on my own experience as a stage IV Melanoma Patient. I wanted to know why my immune system responded and prove to myself and my doctors that it was not a statistical fluke. I dedicate this paper to all my fellow Melanoma Patients that lost their battle with the Beast, especially Bob Luker who fought so bravely but was unable to obtain Anti-CTLA-4 blockade due to the shortage proclaimed by Bristol Myer Squibb which halted compassionate drug use on 9-12-2008.

Most Melanoma tumors are accepted by the host’s immune system and progress even when they contain potentially antigenic proteins. This may be due to the tumor secreting immunosuppressive Cytokines like, TGF-Beta, IL-10, IL-4 and IL-6. TGF-β inhibits the proliferation and functional differentiation of T lymphocytes. TGF- Beta accelerates the expression of CTLA-4 by stimulated CD4+CD25– T cells. TGF- Beta requires CTLA-4 early after T Cell Activation to induce FoxP3 and generates adaptive CD4+CD25+ (Treg) Regulatory Cells. The tumor cells secrete TGF-Beta.

The Making of an Immune Response by Combinatorial Therapy Using Anti-CTLA-4 Blockade and Interleukin-2

“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”
~Charles Darwin~
Take Care,
Jimmy B

Activating the Danger Signal with Anti-CTLA-4 Blockade..Melanoma..Jim Breitfeller

2010-10-08T16:56:00.010-04:00
Melanoma Stats
Initial Diagnosis: May 2003
Current Stage: Stage 4
Depth of Primary: Up to 1 mm
Treatment Stats
Doctor: Mario Sznol MD
Treatment Center: Yale New Haven
Clinical Trial(s): Ipilimumab
Treatment History
February, 2003 my wife noticed a dark spot on my balding head.

April 2003 Punch biopsy read asmelanoma, 0.76mm deep.

May 2003 Wide Local Excision

May-Sept - Multiple dysplastic nevi excised

Sept 2003 - Second primary, this time in situ, on my chest

PET scan, MRI and CT all negative

Oct 2003 - University of Pennsylvania Pigmented Lesion clinic in Philadelphia they reread my slides and reclassified it to a Breslow's depth of 0.86 and Clark's level 4 and told me I have Stage 1B with a specific note that there appeared to be no immunologic response by my body to the melanoma.

October 2003 - October 2006 Derm exam every 3 months. Many dysplastic nevi excised. Doing well, no more primaries, no problems.

October 2006 coughed up blood CT, PET showed a 5cm mass in my L lung. MRI negative for brain mets. No other lesions found.

October 30, 2006 - Thoracotomy at St. Peter's Hospital in Albany NY with removal of the lower lobe of my left lung. Did well after surgery.

November, 2006 - Local oncologist offers interferon but suggests I look into trials

December, 2006 - Accepted into University of Pennsylvania trial of Anti-CTLA4 if my scans remain clear

December 12, 2006 - Had MRI and CT for study and found I has a previously undiagnosed.
met to my brain
December 13, 2006 - Radiation oncologist suggests neurosurgery unless it is not safe to resect. Also heard I may have micro-mets in the lungs. Put on decadron. Seeing neurosurgeon on 12/14

December 14, 2006 - Neurosurgeon says "take it out"

December 20, 2006 - Craniotomy. Second major surgery in 7 weeks! Another stint in the ICU. Woke up unable to move my left leg

December 24, 2006 - One week in a rehabilitation hospital. Intense physical therapy and I walk out

January 2007 - Planned on SRS but more brain mets found. Underwent 15 sessions of WBR

March 2007 - More lung mets found - multiple, disseminated in both lungs, tiny

April 2, 2007 I start IL-2 at Deaconess Beth Isreal in Boston

June, 2007 Brain tumors bleed - emergency craniotomy

July, 2007 - Stereotactic radiation

Sept, Oct waititg for a trial...and waiting...and waiting

October 2007 Accepted in compassionate use trial WITH Ipilimumab (MDX-010 at Yale New Haven Hospital under the care of Dr. Sznol

October 31, 2007 First dose of Ipilimumab at Yale-New Haven Hospital.

November 20, 2007 Second Infusion of Ipilimumab

December 11, 2007 Third dose of Ipilimumab

December 18, 3007 Severe reaction to IPI
Admitted to YNHH with uncontrolled vomiting, dehydration, hyponatremia and weakness. Discharged December 23, 2007 to home. Began 4 mg oral steroids.

January 22, 2008 began to notice double vision, nausea and vomiting as steroids were tapered from 3mg to 2 mg. Steroids increased to 2.5 mg

January 23. , increased to 3mg
anuary 25, increased to 4 mg

January 28, 8 mg January 29 . Nausea and vomiting disappeared. Double vision improvement noted

February 4th…Have lost all peripheral vision.

March 2008 increased weakness noted in lower extremity resulting in confinement to
Wheelchair and walker. MRI noted area of increased swelling on right parietal lobe at site of June 2007 surgery. Not metastatic disease.

April 2008 prescribed high dose (40mg) oral steroids to reduce swelling and manage side effects until planned surgery May 2008.

May 8 2008 planned craniotomy (#3) to remove necrotic tissue iAfter 5 day inpatient stay, walked out of hospital without assistive device. Began taper of steroids.

May-June 2008 unable to tolerate steep taper, steroids increased and taper resequenced at much slower rate.

December 2009 Tumors still visible on scans in brain and lungs but no growth since 2008, Stable. No evidence of active disease.

UPDATE written October 7 2010

October 7, 2010. Four years after my diagnosis with Stage IV Melanoma I continue to show no evidence of active disease. I do have problems elated to treatmens: Simple Partial Seizures, Visual problems (Double and blurred) Short term memory loss, Episodes of fatigue. Symptoms that remind me about what I went through these past four years, but definitely things I CAN LIVE WITH. A hell of a lot better than I thought when I started to fighting the beast/
Mark, Catskill, NY

Activating the Danger Signal with Anti-CTLA-4 Blockade

Was it the combination Radiation, IL-2 plus the Anti-CTLA-4 blockage?

“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”

~Charles Darwin~

Take Care,

Jimmy B

Invoking an Immune Response without causing an Autoimmune Response..Melanoma ..Jim Breitfeller

2010-10-08T11:47:00.009-04:00

Challenges in immunotherapy

• Immunotherapy has yet to fulfil its clinical potential.
• Historically, responses have only been observed in a minority of patients.

• Recent trials of new immunotherapies in oncology have shown that patients receiving treatments such as anti-CTLA-4 therapy respond differently, and sometimes later, compared with those receiving chemotherapy or some of the existing immunotherapies such as interleukin-2 and interferon.

Some of the investigational immunotherapies act as T-cell mediated immunopotentiators. That is, they may regulate and potentially enhance the body’s own immune response, and consequently there may be a delay in stimulating the immune system to fight disease.

"Another patient’s measured tumor burden in 7 pulmonary metastases is shown as a percent of their baseline size. Tumor remained stable during 4 doses of ipilimumab administered without symptoms, but regressed promptly after patient experienced a bout of biopsy documented enteritis." Yang et al
Source:http://pathology2.jhu.edu/hypophysitis/pdf/531_2007_Yang.pdf

en•ter•i•tis ( n t -r t s). n. Inflammation of the intestinal tract.
Inflammation is the "Danger Signal" that is needed to hone in on the cancer itself.

Currently it is difficult to select patients who might benefit from specific immunotherapeutic approaches, and tailored immunotherapy regimens will have to be created in order to provide the most appropriate and effective treatment. Each Patient is at a different stage of his or her disease. It will take a trained Melanoma Oncologist to provide the guidance.

T-cell activation video from Andrew Lamb on Vimeo.

“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”
~Charles Darwin~
Take Care,
Jimmy B

Helper T Cell (Th17) Guides Killer Cells to Melanoma Cancer..Jim Breitfeller

2010-10-05T12:48:00.002-04:00
Cancer manages to suppress or elude the body's immune system to survive and grow. Scientists at The University of Texas M. D. Anderson Cancer Center show this week in the journal Immunity how the helper T cell Th17 awakens the immune system to attack cancer. Senior author Chen Dong discusses the findings and their potential application for patients.

Helper T Cell Guides Killer Cells to Cancer

An important mechanism by which Melanoma cancer avoids antitumor immunity is by recruiting regulatory T cells (Tregs) to the tumor microenvironment. Recent studies suggest that suppressor Tregs and effector Th17 cells share a common lineage and differentiate based on the presence of certain cytokines in the microenvironment. Because IL-6 in the presence of TGF-β has been shown to inhibit Treg development and induce Th17 cells, they hypothesized that altering the tumor cytokine environment could induce Th17 and reverse tumor-associated immune suppression.

CTLA-4–B7 Interaction on the activated T-cell suppresses Th17 Cell Differentiation.Using anti-CTLA4 blocking antibody (Ipilimumab or tremelimumab) increases Th17 cells in peripheral blood of patients with metastatic melanoma. The Th17 cells can then migrate to the tumor's microenviroment. This sends the Danger Signal in the form of pro-inflammatory cytokines including IL-17. This is the third signal that is needed in the initiating of an immune response.

One of the mechanisms proposed is that CTLA-4 inhibition of T cell activation is due to antagonism of CD28-mediated costimulation. Both CD28 and CTLA-4 share the ligands B7.1 (CD80) and B7.2 (CD86); however, the affinity of the CTLA-4:B7 interaction is 10 times higher than the affinity of the CD28:B7 interaction. Although studies using CD28-deficient mice have shown that negative signaling through CTLA-4 is independent of CD28 expression, it is plausible that CTLA-4 interacts with B7 and prevents its interaction with CD28.

It is possible that T-cell activation can’t start until the level of CTLA-4 is block or decreased.

In my own experience, I did not get any activation until tremelimumab was introduced

If you Block the CTLA-4 and B7 with Ipilimumab or tremelimumab It will also take the brakes off the immune system and shift it towards activation.

I hypothesized that Th17 cells induce Th1-type chemokines, and in turn recruit Th1-type effector T cells into tumor microenvironment.

Recent data supports the notion that Th17 cells induce Th1-type chemokines through IL-17 and IFN- , and in turn recruit Th1-type effector T cells and NK cells into tumor microenvironment.

Increased tumor-associated IL-17 predicts improved patient survival

Mechanistically, Th17 cell–derived IL-17 and IFN- synergistically induced the production of CXCL9 and CXCL10, and in turn promoted effector T-cell migration toward tumor. The levels of CXCL9 and CXCL10 were directly correlated with tumor-infiltrating CD8+ T cells and NK cells. The data suggest that Th17 cells may play a role in promoting effector T-cell and NK-cell tumor trafficking and retainment, and the polyfuctional cytokine profile (IFN- +IL-17+) of Th17 cells is essential for synergistically inducing Th1-type chemokines.

Source:http://bloodjournal.hematologylibrary.org/cgi/content/full/114/6/1141

“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”

~Charles Darwin~
Take Care,
Jimmy B

Tregs Rule Unless Anti-CTLA-4 Blockage is Used!!! Melanoma.. Jim Breitfeller

2010-10-01T11:49:00.008-04:00

The first step is to relieve the immune system from the tumor-dependent immune tolerance mediated by Treg, which prevents the development of an efficient antitumor immune response.

The second step is the activation of the immune response.

“It is not the strongest of the species that survives,
nor the most intelligent, but the one most responsive to change.”

~Charles Darwin~

Take Care,

Jimmy B

Beating the Odds.. Did you Ever Wonder??Melanoma..Jim Breitfeller

2010-09-30T11:09:00.005-04:00
Introduction:

"We are pleased to offer you in this website the following prediction tools for predicting the clinical outcome of an individual patient with localized or regional cutaneous melanoma. The prediction tools can be used to predict the 5 and 10-year survival rates from initial diagnosis (with a 95% confidence interval) for an individual patient based on his/her relevant clinical and pathologic information.

The predictive models were developed and validated using a combined database (n=28,047) from 11 major institutions and study groups participating in the development of the 7th edition of the American Joint Committee on Cancer (AJCC) Melanoma Staging System. This database includes 25,734 patients with localized melanoma and 2,313 patients with regional melanoma with relevant information available for model development. For detailed results regarding our prognostic factor analyses, model development and validation, please see the relevant manuscripts listed in the References section. Several additional useful prediction tools currently under development will be added to this website in the near future."

Source:The American Joint Committee on Cancer (AJCC) Melanoma Staging System

Survival Prediction Tool

Now that you have your prediction, it is time to be proactive in your therapy to predict them wrong.

1) Find the best Melanoma Care center that is closest to you
2) Evaluate the Melanoma Oncologist
3) You want cutting edge therapy
4) Get the mutation profile of your tumors
5) Make sure you gather a team of experts
6) Don't take the wait and see attitude
7) Be your own advocate

Here is my prediction based on my intial evaluation.

Estimated Survival Rates
(95% Confidence Interval)

1-Year 2-Year 5-Year 10-Year
87% 76% 53.3% 44.1%
(79.9% - 94.8%) (65.3% - 88.5%) (39.8% - 71.4%) (30.5% - 63.7%)

Keep the Faith!!!!

Jimmy B

“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”
~Charles Darwin~
Take Care,
Jimmy B

Eureka!!!The Right Immune Response..It is All in the Timing and IL-2 Concentration!!! Melanoma..Jim Breitfeller

2010-09-26T14:07:00.019-04:00

So now we have the immune response in full progress. Are we creating the right response?

The difference between CD4+ T-cells and CD8+ T-cells revealed herein must be
interpreted in the context of its significance for the development of an effective
T cell immune response. Within T cell populations, CD4+ T-cells are the primary
source of IL-2 after antigen activation. Consequently, the finding that CD4+ T-cells
cell clonal expansion is only about 25% of the proliferative expansion achieved by
CD8+ T-cells indicates that IL-2 itself is the major parameter retarding clonal
expansion within the total cell population; especially because the rate of T-cell
proliferation is directly dependent on the amount of IL-2 available to the cells. et al Kendall A Smith

The ratio of CD4+ to CD8+ is about 2:1.
Thus, the immunologic relevance of the CD4+ T-cells IL-2 refractory state resides in
its potential as a feedback regulatory control retarding the extent and duration
of IL-2-dependent CD4+ T-cells and CD8+ T cell clonal expansion, ensuring that IL-2-
producing cells ultimately will become limiting.
This interpretation is entirely consistent with observations in lab experiments which indicate that IL-2 rapidly disappears from the culture medium of stimulated T cells.

So what happens if you have excess IL-2 in the Medium?
Studies show that a premature development of CD4+ T-cells IL-2-unresponsiveness arises and the CD4+ T-cells loose their functionality.
This means that premature excess of IL-2 can lead to unresponsiveness of the CD4+T-cells.

Thus, two mechanisms contribute to the depletion of IL-2 from the Medium of rapidly proliferating T cells:

1. The IL-2 internalization and degradation (the uptake) by responding cells
2. The end of CD4+ T-cells + (IL-2 producer) cell proliferative expansion

IL-2 concentration in the surrounding cell environment can regulate the expansion of the CD4+ T-cell population by effecting cell death.
As you keep the IL-2 concentration limiting, you can change the expansion profile if the CD4+T-cells. At low concentrations, the expansion distribution is sharpe and evenly distributive on the time axis. On the hand, at higher or excess concentrations, the distribution becomes skewed, with a longer life cycle.

If the addition of IL-2 is on or before the maximum propagation of the CD4+ T cells, the Tregs population can increase 5-fold in a 96 hour period based on certain growth mediums.
So by increasing the Treg population, you make it that much harder to break the immune tolerance to start an immune response.

So by limiting the excess IL-2 that is introduced into the host at the early expansion phase, you limit the expansion of the CD4+ T-cells. As the Tregs are a subset of the CD4+T-cells, you limit the expansion of the Tregs. By limiting the Tregs and CD4+ T-cells, you limit the CTLA-4 receptors. So blocking the B7 receptors with anti-CTLA-4 antibodies, and limiting the IL-2 in the matrix, you can shift the tolerance balance toward activation.

It is widely accepted that the CD4+ T-cells expand before the CD8+ T-cells.

Activation and Differentiation of (CTLs) Cytotoxic T Lymphocytes

Naïve CD8+ T-cells are referred to as CTL-precursors (CTL-Ps), which are incapable of performing any function other then recognizing the class I MHC-antigen complex on the Tumor cells through the (TCR) T Cell Receptor. For activation, the CTL-P needs at least three signals:

1. Antigen specific signal transmitted by the MHC I peptide/TCR complex for the recognition of the Antigen

2. The Costimulatory signals transmitted by the CD28 receptor and the B7 molecule of the Antigen Presenting Cells (APCs)

3. Cytokine induced signal, IL-2 interaction with the IL-2r (receptor) on the CTL-P leading to activation and differentiation of the CTL-P into effector CTL

The Cytokine IL-2 came from the TH1 cells which means the CTL-P is IL-2 limited and can only be activated by the secreted IL-2 if there is any to be had or by introducing IL-2 through IL-2 therapy. Now you know the reasoning behind using the IL-2 therapy as the second part of the combinatorial Therapy. If there is not enough IL-2 in the host environment, you will only get partial expansion of the CTLs. It may not be enough to eradicate large bulky tumors.

The Interluekin-2 plays another role in this Melanoma Maze. In a study by Janas et al, Il-2 increases the expressions of the perforin and granzyme A, B and C genes in the CD8+ T-cells. This increase expression causes the CD8+ T-cells to mature into Cytoxic T Lymphocytes (CTLs). The exogenous IL-2 is required for the granzyme proteins. CTLs have cytoplasmic granules that contain the proteins perforin and granzymes. A dozen or more perforin molecules insert themselves into the plasma membrane of target cells forming a pore that enables granzymes to enter the cell. Once in the tumor cell, these enzymes are able to breakup (lyse) the cell and destroy it. This is the beginning of the end for the cancer cells. The tumors begin to shrink and the rest is history.

Research suggests that the primary mode of the destruction of the tumors by CTL is by initiating death through the Fas-FasL pathway. Studies have shown that CTLs store Cytotoxic proteins in the form of granules in their cytoplasm. These proteins belong to two categories:
1. Perforins: involved in pore formation
2. Granzymes: responsible for hydrolysis of the cellular products.

Granzymes breaks down the tumors cells just like your detergent enzymes in your laundry detergent.

Immediately following a CTL contact with the tumor cell, the Golgi sacks load with granules and granzymes which create pores to allow the granzymes to enter and destroy the tumors cells.

So what if there is not enough IL-2 produced to supply the overall expansion?

We know the Naïve CD8+ T-cells needs IL-2 for the activation and the differentiation into effector T-cell call Cytotoxic T Lymphocytes (CTLs). We also know IL-2 is needed to upregulate perforin and granzyme A, B and C genes which need to turn the effector cell into a cytotoxic killing machine.

Does the timing of the addition of IL-2 make a difference in the outcome of the immune response?

It surely does. There are a number of research papers that state if the IL-2 is added to early in the expansion phase, you produce non-responsive T-cells. As a matter of fact you could expand the subtype Tregs by a factor 5 under certain conditions. On the other hand, waiting until the expansion is at just passed peak or contracting generates the Cytotoxic T Lymphocytes (CTLs) that we as patients, have been waiting for. That is why Dr. Rosenberg uses IL-2 in his ACT Therapy. It is to generate and maintain the Cytotoxic T Lymphocytes.

Eureka!!!The Right Immune Response..It is All in the Timing and IL-2 Concentration!!! Tumor Shrinkage!!!!
Complete Response!!!!!!

“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”

~Charles Darwin~
Take Care,
Jimmy B

The "Danger Signal" To start the Immune Response...Th17 Cells secreting IL-17..Melanoma Jim Breitfeller

2010-09-24T22:16:00.004-04:00

“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”

~Charles Darwin~

Take Care,
Jimmy B

Living Medical Textbook: Update to the Tumor Immunology and Immunotherapy: Metastatic Melanoma ..Jim Breitfeller

2010-09-24T13:13:00.005-04:00
Living Medical Textbook: Update to the Tumor Immunology and Immunotherapy: Metastatic Melanoma Edition With Dr. Jeffery Weber and Dr. Bernard Fox

Jeffrey S. Weber, MD, PhD
Senior Member, Moffitt Cancer Center
Director, Comprehensive Melanoma Research Center
Professor, Department of Oncologic Sciences
H. Lee Moffitt Cancer Center & Research Institute
Tampa, Florida

Bernard A. Fox, PhD
Chief
Laboratory of Molecular and Tumor Immunology
Providence Portland Medical Center
Earle A. Chiles Research Institute
Portland, Oregon

This "living" textbook is an interactive and up-to-date resource to support learning in the field of tumor immunology, and more specifically focuses on melanoma treatment and management. Throughout each chapter you will find supplemental hyperlinks to external multimedia resources—including illustrations, ...more

Source:http://www.livingmedicaltextbook.org/Activity/index.cfm?jn=2001&sj=2001.01&i=5

You must turn off my playlist by clicking on the radio button on my playlist located on the right column almost all the way down the scrollbar

Listen as Dr. Weber interviews Dr. Fox about the ability of helper T cells, cytolytic T cells, and natural killer T cells to mediate tumor regression.

Listen as Dr. Weber interviews Dr. Fox about the ability of regulatory T cells to dampen the immune response to tumor cells.

Listen as Dr. Weber and Dr. Fox discuss investigational immunotherapies that improve T cell targeting of tumors.

Special Feature: Replay the complete audio interview between Dr. Weber and Dr. Fox

“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”
~Charles Darwin~

Take Care,

Jimmy B

The missing third signal "The Danger Signal"Melanoma..Jim Breitfeller

2010-09-21T19:58:00.006-04:00
Th17 Cells Secrete IL-17 in the Tumor Microenvironment causing inflammatory symptoms "The Danger Signal"improves Survival in a Murine Model of Pancreatic Cancer and in Melanoma also.

Third, inflammatory cytokines, including IL-1, IL-6, IL-12, and IFN-γ provide a third signal that acts directly on T cells, referred to as the “danger signal”. This signal was found to optimally activate TH1 differentiation and lead to clonal expansion of T cells.

"Th17 cells and IL-17 participate in antitumor immunity by facilitating T cell recruitment to the tumor site and CD8+ T cell priming and effector differentiation suggests a new avenue for developing Th17 cell-based therapy."

~S. A. Rosenberg~

"Using in vitro and in vivo approaches, we determined that under neutral conditions, simultaneous activation of Tregs and naive CD4+ conventional T cells in the presence of APCs resulted in conversion of Tregs into IL-17–producing cells, and endogenous IL-1β was mandatory in this process" according to Vassiliki A. Boussiotis et al

Thus, the addition of IL-6 and IL-1β to the tumor microenvironment skews the balance toward Th17 cells in a murine model of pancreatic cancer and Melanoma.

So we need to suppress the Tregs and generate Th17 T-cells to initiate the right immune response.

“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”
~Charles Darwin~
Take Care,
Jimmy B

New Drugs Stir Debate on Rules of Clinical Trials..Melanoma - Jim Breitfeller

2010-09-20T08:33:00.006-04:00
New Drugs Stir Debate on Rules of Clinical Trials..Melanoma -

New Drugs Stir Debate on Rules of Clinical Trials..Melanoma PLX4032

We should let the FDA ,Congress and Plexikkon know how us, the Patients feel about the clinical trial protocol process.
It doesn't smell right.

Stop monkeying round with Our Life. We are just trying to survive.

Peter Hirth CEO Plexxikon

Try These. I am not sure of the CEO’s email. Just try and see if they bounce back.

kphirth@plexxikon.com CEO

phirth@plexxikon.com CEO

kglaub@plexxikon.com President

Richard Pazdur
Richard Padzur to run its new Office of Oncology Drug Products (OODP)
pazdurr@cder.fda.gov

Plexikkon should open a compassionate care use to the patients that have no other trial available.Peter Hirth, show some compassion to your customers/patients.

Please Make the right choice!!!

Please write about your disgust to the above email addresses

Thanks in advance

“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”
~Charles Darwin~

Take Care,
Jimmy B