Combinatorial Therapy Will Revolutionize Cancer Therapy ...Just wait until ASCO 2015!!

Bristol-Myer Squibb Pharmaceutical Research Institute
Attention: Elliott Sigal
Route 206, Provinceline Road
P.O. Box 4000
Princeton, New Jersey 08543 U.S.A...

 Date: 3-10-2010

Dear Dr. Sigal:
I want to thank you for responding to my emails over the last few months. I know I can be candid and straight to the point sometimes. By reopening the compassionate Drug Use (ipilimumab) you and your company gave the Melanoma Patients “The Last Chance of HOPE”. You don’t know how much this means to us. If we haven’t passed the “Lethal Tumor Burden” we still have a chance of survival. I believe you have done your company justice and showed your compassion. My faith in the Company’s Ethics has been restored.

Now we need to prove to the world that this drug may be one of the most important discoveries in the last twenty years of Cancer. By taking the “Brakes off the Immune System” we can harness our own immune system to battle cancer. Granted we may have to use the drug in combinatorial therapy to rid the host of the cancer once and for all. I hope you and your company can collaborate together with all the major players in this exciting field of Oncology. See it took millions of years for our immune system to evolve, so why do we think that one drug can do it all. We need to approach the Beast arm to arm, to block all the pathways so it can’t escape. This can only be done by using one’s own immune system.

Can you imagine working out a protocol that will vaccinate the patient with the patients own tumor–specific antigen? And Ipilimumab (Anti-CTLA-4 Blockade) is at the center of this revolutionary therapy/protocol. Please if you get a chance, listen to some of the lectures and symposiums from the like of Dr. James Allison, Dr. Jedd Wolchok, Dr. Antonio Ribas, Dr. Jeffery Weber, Dr Keith Flaherty and others. You will be amazed at their accomplishments in the clinical setting. But they need more. They need access to the entire drug arsenal that is available across companies. We now know that timing and dose concentration plays a major roll in setting up an immune response. There are feedback loops. It is like dominos. You have this elaborate step-up. It may take weeks to build. Once you set it in motion, the chips begin to fall. There are different pathways, cytokines, T-cells, receptors, etc that need to be taken into account get the right immune response. This immune response can only be generated if you have all the keys to unlock the response. We need yours and other Pharmaceuticals to work together for the good of the cancer patients. We need to take down all the red tape which also includes the FDA.

“Our Life depends on it.”

Thanks again.
Sincerely,
Jim Breitfeller

 

 

“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 2013.. The comming out party for Combination Therapy!!! Yervoy + Anti-PD-1 ..Melanoma. Jim Breitfeller

ASCO 2012 was PD-1’s debutant ball, but we may have found a partner (Yervoy) at this Year’s 2013 Ball and may be only a few years away from its coronation (FDA’s approval) as a stand alone or combinatorial therapy. I believe that ASCO 2013 will be the coming out party for combination therapy of Anti-PD-1 + Yervoy.

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Using this combination blocks two checkpoint pathways on the T-Cells leaving it activated to proliferate and destroy the cancer.

If you add Yervoy & Anti-PD-1 to the therapy you have a better chance to activate the CD4 and CD8 T-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

 

How to integrate immunotherapies into treatment timelines? Timing is everything! Melanoma..Jim Breitfeller

Dr. Gomella,

I want to thank you for sharing your thoughts on immunotherapy in the article in “High Points and Hurdles: Immunotherapy Moves Forward” online at OncLive.

As a patient/survivor/researcher of stage IV melanoma I know first hand of the importance of integrating immunotherapy into a patient’s treatment. Timing of the therapy is everything, along with the patient’s tumor burden and stage.

In the early phase of cancer, the tumor cells are trying to establish a foothold in a foreign land. They do this by recruiting Tregs with cytokines (Il-10, TFG-b etc.) along with chemoattractants and suppressive cells.

Two of the first arrivals are Tregs along with IL-10. In the early phase of cancer, it has been discovered that the patient’s Tregs are elevated along with IL-10 concentration.

So when the macrophages and immune cells arrive at the tumor’s microenvironment, they encounter suppressive conditions allowing the tumor to continue with growth and progress. The elevated IL-10, IL-4 concentration polarizes the monocyte to the M2, and the T-cells to the Th2 phenotypes and shutting down the immune response.

The macrophage also secretes some chemokines (CCL17, CCL22& CCL18). These chemokines attract other cells that have the cell surface chemokine receptors such as CCR4.


Treg cell migration to Melanoma tumors is mediated by CCL22 released by cancer cells and tumor-associated macrophages. This cytokine plays a role in the trafficking of activated/effector T-lymphocytes to inflammatory sites and other aspects of activated T-lymphocyte physiology. Chemotactic for monocytes, dendritic cells and natural killer cells. Mild chemoattractant for primary activated T-lymphocytes and a potent chemoattractant for chronically activated T-lymphocytes but has no chemoattractant activity for neutrophils, eosinophils, and resting T-lymphocytes This attraction is the beginning of the suprresiveness of the the tumor’s microenviroment.

TAM exert strong immune suppressive activity, not only by producing IL-10 but also by the secretion of chemokines (e.g., CCL17 and CCL22), which preferentially attract T cell subsets devoid of cytotoxic functions such as Treg and Th2.


IL-10 promotes the development of a type 2 cytokine pattern by inhibiting the IFN-γ production of T lymphocytes particularly via the suppression of IL-12 synthesis in accessory cells.

IL-10 suppresses many functions of (NK) cells and T cells, primarily by preventing APCs from producing proinflammatory cytokines

So how can we integrate immunotherapies into treatment timelines to generate the wanted immune response toward the cancer?

1. First, you need to evaluate the cancer patient and establish their stage.
2. Second, check the tumor’s genetic code for mutations.


3. Third, evaluate the patient’s overall health and the ability to go through the therapy
   
   Here is a generic graphic on how to activate an innate and adaptive response.

1) You need to generate tumor-associated Antigens


2) You need to generate “The Danger Signal” (proinflammatory cytokines secreted, IL-1, IL-6, IL-12, TNF-alpha, Nitric Oxide, PGE2)

3) Block the Suppressive factors that inhibit T-cell activation (Anti-CTLA-4, Anti-PD-1, Anti IL-10r) IL-10 suppresses many functions of (NK) cells and T cells, primarily by preventing APCs from producing proinflammatory cytokines, “The Danger Signal”)

4) Tilt the T-cell Differentiation toward the TH1 phenotype and the Macrophage (TAM), Tumor Associated Macrophage polarization toward the M1 phenotype

5) Alter the tumor’s Microenvironment (addition of Multikine)

6) Produce activated CTLs and Memory T-cells(addition of IL-2)

The Bottom line is we need Sequential Combinatorial Therapy with timing and dosage as the major limiting factors in creating the innate and adaptive 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

Legislation for Combinatorial Therapy >> Melanoma ..Jim Breitfeller

Congressman Bilbray, and Congresswomen Maloney and DeLaura are submitting legislation today that, if passed, will provide extended patent protection for investigational drugs that are tested in combination. This will provide a major financial incentive for industry to do the kinds of studies they now find difficult but which offer the best hope for melanoma patients. This legislation came out of meetings MRF had with Congressman Bilbray, whose daughter has Stage III melanoma. We proposed the idea to the Congressman and provided a background document showing how similar action in pediatrics and some infectious diseases has resulted in tremendous progress in drug development. Most doctors agree that real advances in effective treatments will only come through combining two or more drugs together. If these drugs are already approved, doing studies like this are relatively easy. If they are not yet approved--still in clinical trials--they are very difficult. Companies worry that any side effects that arise from a combination study will "taint" the data of their drug and hurt its chances of approval. And they are reluctant to collaborate with other companies on these studies. This legislation will add a "carrot" to the mix and will help accelerate these important studies.

“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

You and Your Doctor—Tackling Your Cancer Together..Melanoma..Jim Breitfeller

You and Your Doctor—Tackling Your Cancer Together

 Talking with your doctor openly about your diagnosis and treatment—and keeping informed every step of the way—will help you work with your doctor to make the best possible decisions about your treatment.

 Educate yourself


 Visit websites designed to educate and assist patients with your type of cancer.

 Ask your doctor where you can learn more about your cancer, its treatment and any ongoing research.

Be informed when you talk to your doctor and treatment team.

Ask questions and be proactive.

It’s your health—and your life!

Talk openly with your doctor Molecular testing for cancer-related genes may not be right for everyone, but by staying informed and asking about such testing, you can be sure that every avenue for treating your cancer has been explored. And for you, that may make the difference between treatment that is effective, or not.


Here are some questions you might ask your doctor:

Are there gene mutations identified for my type of cancer?
 Should my tumor be tested for gene mutations?
What can molecular testing tell me about my cancer?
What can molecular testing tell me about my prognosis?
How might molecular testing affect my treatment plan?
How can I get my tumor or biopsy tested?

 “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

 

Trying to take the guess work out of finding the correct immunotherapy for Melanoma Patients.Jim Breitfeller

As a stage IV survivor/researcher of Melanoma, I know first hand how it feels to be diagnosed with stage IV cancer. You, your family and your caretaker becomes overwhelmed by the information that must be absorbed and processed to make an educated decision on what therapy you want to try. Don’t get me wrong, your oncologist will play a major in your decision, but is it the right one? Is he trying to fill some of his clinical trials or is he looking out for your best interest? Armed with the right information, one can make the best possible choice. It shouldn’t be a hit or miss approach because with cancer, time is of the essence. Getting to the right therapy before you end up at the late stage IV of your disease is the name of the game. In my therapy, that was my goal, find the right therapy before it overcomes your internal organs and kills you. So, in 2005, I asked my doctor John M Kirkwood if they would take my tumors and biopsy them for gene analysis. Back in 2005, this analytical activity was revolutionary and not done as a standard of care. So in 2005, I contacted Arlet Alarcon from the Molecular Profiling Institute. I tried to convince Dr. John M. Kirkwood, but it was not to be. But now to fast-forward to 2012 and you will see molecular profiling your tumor becoming common practice. So with this in mind, here are some suggestions to get you on the right path. 1.) Assemble a team of doctors that specialize in your cancer. 2.) Make sure they see you as a major part of the team and the decision making. (Be your own advocate) 3.) Learn the medical language so you can research and stay abreast of the new therapies that are being discovered daily. 4.) Learn how your immune system works and how the therapies interact with the immune system. 5.) Be POSITIVE!!!
Here is the latest slide from "Evolving Treatment Options in Melanoma: Utilizing Genetic Features to Optimize Therapy" by Dr. Ribas

permission granted from Clinical Care Options – Oncology http://www.clinicaloptions.com/oncology.aspx SOC= Standard of Care

What I am trying tell is that by optimizing your personal therapy, you can extend your survival. “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 very Happy Father's Day from a stage IV Melanoma Survivor..Jim Breitfeller

I want to thank all the people that has made this day a very special Day.


As a stage IV Melanoma Survivor, I never dreamed that I would be here today to witness my children spread their wings and learn to fly. My daughter was just entering college when I was first diagnosed and my son, Chris was a sophmore in High School. Today, I am preparing to help my son relocate to Connecticut. He just landed an engineering job at an areospace company. My daughter, Jessica is globe-trotting around the world working on her dual Masters in "International Affairs" and "Natural Resources & Sustainable Development". This day, marks Dee and I as offically "Empty Nesters".

This all was made possible by entering a journey that entailed four clinical trials along with the best and internationally renowned medical team that makes climbing Mt. Everst apiece a cake. And you , My carepage friends that kept me on the "Yellow Brick Road". I have won the "lottery of life."

Many Thanks

“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
 

Anti-PD-1 (BMS-936558, MDX-1106) in patients with advanced solid Melanoma tumors: Clinical activity, safety, and a potential biomarker for response.Melanoma ..Jim Breitfeller

I have been following this new treatment for a number of years and am trying to get my arms around the science.

When a T-cell is activated, the PD-1 , CTLA-4, ICOS, and others molecule are expressed and upregulated to the surface of the T-cell. Both PD-1 and CTLA-4 are checkpoint molecules that regulate the immune response. They are inhibitory to the point that they can shut down T-cell activation. ICOS on the other hand is a costimulatory molecule that is needed, along with IL-2 to keep the T-cell activated and help proliferate the T-cells.Elevated levels of ICOS mRNA can be detected already one hour after TCR engagement, followed by surface expression within 12 hours. Protein expression reaches a maximum after 48 hours and declines then slightly.

It has been shown that ICOS is inducible within 48 hours of T  cell activation on both CD4+ and CD8+ cells  after  CD28 signaling  whereas cytotoxic T lymphocyte  antigen-4 (CTLA-4) ligation prevents its upregulation.

First, CTLA-4 engagement on resting T-cells was found to indirectly block ICOS costimulation by interferring with the signals needed to induce ICOS cell surface expression. Second, on preactivated cells that had high levels of ICOS expression, CTLA-4 ligation blocked the ICOS-mediated induction of IL-4, IL-10, and IL-13, suggesting an interference with downstream signaling pathways. The addition of IL-2 not only overcame both mechanisms, but also greatly augmented the level of cellular activation suggesting synergy between ICOS and IL-2 signaling.

So after T-cell Activation, IFN gamma is secreted (30 minutes), then IL-2 is secreted (45 minutes in) and so on,

The surface expression of ICOS is within 12 hours of activation. Since CTLA-4 blocks ICOS costimulation, Yervoy (anti-CTLA-4) must be used to counter the surpressive signalling. PD-1 also upregulates to the surface in the early activation process. PD-1 is upregulated within 24h after T cell activation.PD-1-Mediated Suppression of IL-2 Production Induces CD8+ T Cell ... anergy was associated with a marked down-regulation of IL-2.

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.

PD-1 blockade seem to augment the proliferation of the CD4+ helper cells.

Now you know why just using Anti-PD1 and or Yervoy as a monotherapy will not have a large response rate. Combinational Therapy is a must if we are to see synergistic responses. IL-2 also plays a major roll in the immune response. IL-2 is added to help maintain fuctionality and survival of the Cytotoxic T Lymphocytes (CTLs) that is despartly needed to eradicate the Melanoma tumors. Our immune system can cure cancer, I am living proof of it.

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

Immunotherapy of cancer in 2012..Melanoma ..Jim Breitfeller

This is a great summary of Immunotherapy as we know it today. A must read for cancer patients, caregivers, Oncologists.

Download it today!!!
Melanoma Immunotherapy of cancer in 2012

It is somewhat technical but should be in the patient's, caregiver's and Oncologist's library. Knowledge is power. Power to heal ones disease.


“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 melanoma treatment -- a turning point against cancer? Jim Breitfeller

This is not new!! If you read my paper "Melanoma and the Magic Bullet" from the shared files, you will see that I was able to shed tumor antigens using Chemotherapy.

New melanoma treatment -- a turning point against 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

Radiation Blast May Turbocharge Bristol-Myers Melanoma Drug, Report Shows..Jim Breitfeller

Radiating one tumor can trigger the immune system to wipe out tumors in other parts of the body and may boost the effectiveness of Bristol-Myers Squibb Co. (BMY)’s cancer drug Yervoy, doctors have shown.
Source: Radiation Blast May Turbocharge Bristol-Myers Melanoma Drug



Recent evidence shows that the anti-tumor immune response elicited by radiation therapy or chemotherapy is due to the release by dying tumor cells of HMGB1, which acts on TLR4/MyD88 on dendritic cells.

It has been known that if radiation kills the outer most cells of the tumor, it can shed tumor specific peptides/antigens that are picked up and display on the DCs. It can also get the cells to secrete HMGB-1 which binds to the TLR4 and activates the macrophages which in turn secrete IL-12 and other cytokines and chemoattractants to get the right immune response.



Dr. Rosenberg uses whole body radiation prior to the adoptive cell therapy. He has seen higher responses.

The Immune System needs three Signals:

The role of the CD8+ T cells is to monitor all the cells of the body, ready to destroy any that express foreign antigen fragments in their class I molecules.

Three major events must occur to Activate CD8+ T cell mediated response against melanoma.

First, the T-cell receptor (TRC) must be triggered by a (or multiple) self antigen–derived peptide MHC class I complex. This event depends entirely on appropriate antigen presentation, which is most efficiently provided by mature dendritic cells. 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 . 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.

Without the tumor derived debris(Tumor-specific antigens), the immune system doesn't know what to go after.No Immune response will occur.

new-melanoma-treatment-a-turning-point-against-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

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

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

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

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

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

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

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

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

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

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

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

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

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

CTLA-4 Ligation Blocks CD28-dependent T Cell Activation..Melanoma.Jim Breitfeller

CTLA-4 Ligation Blocks CD28-dependent T Cell Activation


Summary:
CTLA-4 is a CD28 homologue beheved to be a negative regulator of T cell function. However, the mechanism of this downregulatory activity is not well understood. The present study was designed to examine the effect of CTLA-4 ligation on cytokine production, cell survival, and cell cycle progression. The results demonstrate that the primary effect of CTLA-4 ligation is not the induction ofapoptosis. Instead, CTLA-4 signaling blocks IL-2 production, IL-2 receptor expression, and cell cycle progression of activated T cells. Moreover, the effect of CTLA-4 signaling was manifested after initial T cell activation. Inhibition oflL-2 receptor expression and cell cycle progression was more pronounced at late (72 h) time points after initial activation. The effects of anti-CTLA-4 mAbs were most apparent in the presence of optimal CD28-mediated costimulation consistent with the finding that CTLA-4 upregulation was CD28-dependent. Finally, the addition of exogenous IL-2 to the cultures restored IL-2 receptor expression and T cell prohferation. These results suggest that CTLA-4 signaling does not regulate cell survival or responsiveness to IL-2, but does inhibit CD28-dependent IL-2 production.


CTLA-4 Ligation Blocks CD28-dependent T Cell Activation


“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

ICOS is the first immunologic marker to be identified in patients treated with anti-CTLA-4 ..Melanoma ..Jim Breitfeller

ICOS is the first immunologic marker tobe identified inboth tumor tissues and the peripheral blood of patients treated with anti-CTLA-4

Increased ICOS expression is detected on CD4 and CD8
T cells after treatment with 10 mg/kg/dose of anti–CTLA-4
antibody.

An increased and sustained frequency of CD4+ICOS hi
T cells correlated with improved overall survival.

At 10 mg/kg/dose Ipi, CD8+ICOS hi T cells were detectable in tumor tissues
At 3 mg/kg/dose Ipi, CD8+ICOS hi T cells were undetectable in tumor tissues
untreated patients, CD8+ICOS hi T cells were undetectable in tumor tissues

Preoperative CTLA-4 Blockade- Tolerability and Immune
Monitoring in the Setting of a Presurgical Clinical Trial



Preoperative CTLA-4 Blockade: Tolerability and Immune
Monitoring in the Setting of a Presurgical Clinical Trial


This is why the dose should be at least 10mg/kg not 3mg/kg.

Bristol Myer Squibb, please take note!!!!


“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