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

Interview With Michael B. Atkins, MD Immunotherapies in Melanoma.Jim Breitfeller

Interview With Michael B. Atkins, MD Immunotherapies in Melanoma: Taking Stock
 Alice Goodman, MA; Michael B. Atkins, MD

 Posted: 07/02/2012

 Editor's Note: Immunotherapy is the only treatment that can produce durable tumor regression in patients with metastatic melanoma. With novel molecularly targeted agents also being developed for metastatic melanoma, the hope is to learn how to combine and sequence these therapies and improve survival for patients with this once universally fatal disease. At the 2012 annual meeting of the American Society of Clinical Oncology (ASCO®), Dr. Michael B. Atkins, Deputy Director of the Georgetown Lombardi Comprehensive Cancer Center in Washington, DC, chaired an educational session on immunotherapy in advanced melanoma.

 Medscape caught up with Dr. Atkins to ask him to put into perspective the emerging data on immunotherapy and what questions still need to be answered.

IL-2 Opens the Door Medscape:
 What was the first immunotherapy to show an effect in metastatic melanoma?

Dr. Atkins: High-dose interleukin (IL)-2 received US Food and Drug Administration (FDA) approval for the treatment of patients with metastatic melanoma in 1998. A number of durable responses were observed and 11% of patients were alive at 5 years.[1] More recent studies have shown that patients with elevated lactate dehydrogenase (LDH) levels are much less likely to respond to IL-2, with about a 6% response rate in patients with elevated LDH (all partial responses) and about 21% in those with normal LDH levels.[2] Analysis of molecular profiles shows that a significantly larger proportion of patients with BRAF- and NRAS-mutated tumors respond to IL-2 than those who do not have these mutations. Also, we now have information suggesting that tumors with an inflamed phenotype and immune infiltrates have a 2- to 3-fold improved chance of response relative to those with a noninflamed gene expression pattern.

Michael B. Atkins, MD
Medscape: Has IL-2 been combined with other immunotherapies?

Dr. Atkins:
 IL-2 has been combined with vaccine therapy. Results of a randomized trial found that the combination of IL-2 plus vaccine produced response rates of 22.1% compared with 9.7% with IL-2 alone, and a trend was observed toward improved overall survival.[3] Median survival was 17.6 months with the combination of IL-2 plus vaccine vs 12.8 months with IL-2 alone. Very few relapses were seen beyond 2 years in responding patients, a hallmark of effective immunotherapy. However, lower-than-expected response rates were reported for the IL-2-alone group, calling into question how much of an advance this treatment is. Some questions remain: Is this a proof of concept that the immune response can be focused by a vaccine? Will the findings be relevant with novel immunotherapies? Ipilimumab: A Check-Plus for a Checkpoint Inhibitor Medscape: More recently, ipilimumab, a different type of immunotherapy, was approved by the FDA for the treatment of metastatic melanoma. This drug is referred to as the first checkpoint inhibitor, meaning that it interferes with an important downregulatory property of the immune response.

How does this drug work, and what kinds of outcomes does it achieve?

Dr Atkins: The monoclonal antibody ipilimumab blocks CTLA-4, which serves as a coregulatory protein that shuts off the immune response when it binds to a protein on antigen-presenting cells. Blocking CTLA-4 restores immunity. Ipilimumab has been evaluated in a variety of clinical trials. It is administered intravenously once every 3 weeks for 4 doses on an outpatient basis. Its side effects result primarily from induction of immune reactions against normal tissues, but in general, it produces fewer inflammatory systems (eg, fever, chills, hypotension) than those associated with high-dose IL-2. A recent trial compared ipilimumab plus gp100 vaccine vs ipilimumab alone vs the vaccine alone.[4] In both ipilimumab-containing arms, survival was prolonged. One-year survival was 46%, 44%, and 26% for the 3 arms, respectively. Two-year survival was 22%, 24%, and 14%. Few deaths occurred in the ipilimumab-treated patients after 30 months.

Medscape: What about the safety profile of ipilimumab and patient selection?

Dr Atkins:
The toxicities of ipilimumab are related to activation of the immune system and include colitis, dermatitis, endocrine effects, and hepatitis. In clinical trials, all subgroups benefitted from ipilimumab, with the possible exception of patients with elevated LDH. One feature of ipilimumab is apparent disease progression early in the course of treatment followed by a major response, so we have learned that the effect of treatment is not seen immediately. Pooled data from clinical trials suggest that about 25% of patients with metastatic melanoma have long-term benefit from ipilimumab therapy, and the benefit might be greater with a higher dose of the drug. Also, there is a potential role for maintenance therapy with this agent.

Medscape: Has ipilimumab been studied in combination therapy?

Dr Atkins:
A study was conducted in previously untreated patients with metastatic melanoma in which the patients were randomly assigned to dacarbazine alone or dacarbazine plus ipilimumab.[5] Some experts expected better results than were achieved in this first-line setting, and it is possible that dacarbazine may have compromised outcomes.

Medscape: What are the take-home messages about ipilimumab for metastatic melanoma?

Dr. Atkins:
Ipilimumab enables an immune response and antitumor responses in some individuals. This agent is powerful enough to work in the central nervous system and overcome concurrent immunosuppression. The response to ipilimumab may be associated with autoimmunity. Activity of the drug is seen in patients previously treated with IL-2. This drug is an option for most patients with advanced melanoma. Optimal timing of therapy and severe autoimmune toxicities should be considered. We don't know the answers to all of the questions about how to use ipilimumab. Should it be combined with dacarbazine? Should it be used as first-line or second-line treatment? What is the optimal dose and schedule? Does it have a role in maintenance therapy? What is its role in the adjuvant setting? What combinations should be studied? Some possible combination partners are bevacizumab, GM-CSF [granulocyte-macrophage colony-stimulating factor], high-dose IL-2, and the novel PD-1 antibody. PD-1 Inhibitor: New Kid on the Block Medscape: At the 2012 annual meeting of ASCO®, we heard exciting preliminary reports about a second checkpoint inhibitor called MDX-1106, a PD-1 antibody.

 How does this immunotherapy work, and what are preliminary observations?

 Dr. Atkins:
On activated T-cells, PD-1 serves as the receptor for PD-L1, which is expressed on tumor cells. When PD-L1 binds to PD-1 inside the tumor microenvironment, it paralyzes T-cell immune function. Blocking the interaction between PD-L1 and PD-1 with an antibody provides a specific way to activate the immune system within the tumor microenvironment. It is hypothesized that this would provide a less toxic and more potent means of activating the immune system. Several presentations at ASCO® on this novel immunotherapy showed exciting preliminary results. A large phase 1 study evaluated MDX-1106 given every 2 weeks for up to 2 years in patients with melanoma, renal, and non-small cell lung cancer.[6] Durable responses were seen in all 3 malignancies. In the melanoma patients, about half had tumor shrinkage and some responses were quite significant. This novel therapy will move forward in clinical development for patients with melanoma, either as a single agent or in combination. A number of PD-1 and PDL-1 blockers are under development. Which Patients Are Right for Immunotherapy?

Medscape: How do you select patients for treatment with immunotherapy?

 Dr Atkins: Patients with metastatic melanoma are not all the same. There are 2 basic phenotypes: noninflamed and inflamed. Data suggest that the second phenotype is associated with a better prognosis; that is, the greater the percentage of immune cells within a tumor, particularly CD8+ T cells, the better the prognosis. As mentioned previously, patients with tumors expressing an immune signature are more likely to respond and to exhibit a longer progression-free survival than those with tumors that do not have this signature. Studies suggest that PDL-1 expression appears to be associated with benefit, because patients without PD-L1 expression were less likely to respond to PD-1 antibody.[6-8] Sequencing: Which Therapy, and When? Medscape: What is the current thinking on sequencing of therapies? Dr Atkins: In addition to immunotherapies, several new targeted therapies are on the horizon. Vemurafenib, which targets tumor containing a BRAF V600E mutation, is approved for the treatment of patients with metastatic melanoma, and other BRAF and MEK inhibitors are being studied. These therapies may be able to be used in combination with immune therapies to improve outcomes. Most patients would like a chance to be cured. Immune therapies are the only curative therapies for advanced melanomas. Thus, if patients can receive an immune therapy, it may be better to give it first. For BRAF wild-type tumors (those without the BRAF V600E mutation) and even for the BRAF-mutated tumors, it might make sense to give patients an immunotherapy first to try to produce long-term benefit and reserve the use of a BRAF inhibitor for those patients who don't respond to immunotherapy. Data suggest that giving an immunotherapy first does not reduce the ability to respond to a BRAF inhibitor. On the other hand, patients who progress on vemurafenib do not appear to respond to ipilimumab. In fact, in a small study of 32 patients whose disease progresses on vemurafenib, 50% were dead within 4 months.[9] Only 3 of the 32 patients were alive longer than 1 year, and all of them were back on a BRAF or a MEK inhibitor. These preliminary data suggest that a BRAF inhibitor may not be the best initial therapy for some, if not most, patients with BRAF V600E mutations. A prospective trial is needed to study this question. A sequencing study is being planned by ECOG that has 2 arms: ipilimumab with crossover to vemurafenib at time of progression vs vemurafenib with crossover to ipilimumab at time of progression. The primary endpoint will be overall survival at 2 years. The study should tell us which is the best initial therapy for patients with BRAF mutant metastatic melanoma.

More Work to Be Done Medscape: Are there any potential downsides to combining immunotherapy and targeted therapy?

Dr Atkins: By combining immunotherapy and targeted therapy, the hope is to get the benefits of both worlds. But there are potential problems. Studies suggest that dacarbazine interferes with the immune effects of ipilimumab; however, preliminary data suggest that BRAF inhibitors might increase immune infiltration into tumors, converting the microenvironment from a noninflamed state to an inflamed state. Theoretically, this might mean that the combination of a BRAF inhibitor with immunotherapy might produce synergistic antitumor benefits. Medscape: What can you say to sum up where we are with melanoma immunotherapy in 2012? Dr Atkins: We have IL-2 and ipilimumab, and there are novel immunotherapies on the horizon, including the PD-1 antibody. We will need studies to refine optimal patient selection and identify the best combination treatments, including a BRAF inhibitor either alone or in combination with MEK inhibitors. The field has advanced, and in 2012 it is no longer futile to treat metastatic melanoma. There is a glimmer of hope on the horizon, but there is still a lot of work to be done.

Source: http://www.medscape.com/viewarticle/766473?src=mp&spon=38

“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

Complexities of cancer elude magic bullet..Melanoma ..Jim Breitfeller

Complexities of cancer elude magic bullet


"True change will entail extending survival not by months, but by years, moving ever closer to the five-year cancer-free mark that is considered a cure. Unfortunately, this remains an elusive goal for many types of cancer due to the near inevitability of recurrence.
The reasons for this are many and controversial, but few dispute that the problem lies in the complexity of cancer, the growth and metastasis of which involve multiple processes, pathways and cell types. Because most drugs target only one of the many factors that give rise to cancer, it is not surprising that the disease so commonly displays an aptitude for evading them.
Given cancer's complexity, most agree that the long-coveted cure will be found not in a magic bullet, but in a combination of bullets aimed simultaneously at several specific targets. Here, immune-based drugs present a number of distinct advantages: their favorable safety profile is conducive to combination therapy, and a number of different immunotherapy candidates have shown promising activity against well-established tumor targets.
However, because the U.S. Food and Drug Administration requires each of these experimental treatments to be tested individually, it is far from clear that any of these products alone could pass the demanding test of significantly improving overall survival - even if there is good reason to believe that they could provide significant benefit together. " ~Swiss Trader~

We need the FDA to consider Combinatorial Therapy as a new Product/Process that is capable to win this war on Cancer.
I have lived it first hand, and have benefited from this form of therapy. It was no fluke that I was able to jump-start my immune system. With the help of my Oncologist we were able to string the right clinical trials together to produce the right immune response. Some day we will all look back to this day and say to ourselves, why did no one take notice.
The CURE is right under our noses. Think outside the box!

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
 

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

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

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

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

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

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

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

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

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

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

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

Late-Breaking Abstracts..Melanoma ..Jim Breitfeller

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

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

“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

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

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

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

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