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

Immunotherapy.. The Magic Bullet.. The Breakthrough Therapy.. the Paradigm Shift.. The Future

I wrote about this as the "Magic bullet" back in 2009.Great insight in where immunotherapy is heading in the future.



When you combine anti-CD47 therapy with checkpoint therapy (anti-PD1 and or anti-CTLA4/Yervoy), you involve the innate and the adoptive immune system to eradicate cancer (Melanoma)
 I would like to see combinatorial therapy with checkpoint inhibitors like yervoy/anti-CTLA-4 & anti-PD-1along with anti-CD47 to eliminate the "don't eat me" signal, so the macrophages can get involved with the tumor elimination.

http://www.youtube.com/watch?v=XGeqAEr1RnE&feature=share


“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

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

 

ACTION! Help Save the Life of Darcy Doherty, Father of Three Children to get immunotherapy drug for melanoma..Jim Breitfeller

ACTION! Help Save the Life of Darcy Doherty, Father of Three Children to get immunotherapy drug Anti-PD-1 (BMS-936558)  for melanoma.




Please write to Dr. Elliot Sigal at Bristol Myer Squibb
Elliott.Sigal@bms.com

Dr. Sigal is the Director of Research at BMS.
Please send a note to Dr. Sigal requesting that BMS open compassionate use for Mr. Doherty. I know it is a long shot/ Hail Mary Pass but, base on my research, this drug with the combination of IL-2 may be able to beat the odds.

Bristol Myer Squibb says "At Bristol-Myers Squibb, we are firmly focused on our Mission to discover, develop and deliver innovative medicines that help patients prevail over serious diseases."

Is this all lip service? Let see if BMS puts their money where their mouth is and grant this compassionate care use for this derserving family. Doherty with his clinal trial of Yervoy (Anti-CTLA-4 therapy) helped get the drug FDA approved through his survival data. The least Bristol could do is to grant the dying man compassionate use of the next generation drug called Anti-PD-1, (BMS-936558)

Bristol-Myer Squibb needs to show some compassion.

It is their ETHICAL Responsibility.


“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
 

Dying man fights to get experimental drug from Bristol-Myers Squibb..Melanoma ..Jim Breitfeller

Emily Jackson Staff Reporter Darcy Doherty’s last chance at life lies in an experimental drug. The yet-to-be-approved treatment is the only option left for the 48-year-old father of three with metastatic melanoma, believes his oncologist Dr. David Hogg, an attending physician at Princess Margaret Hospital. But maker Bristol-Myers Squibb (BMS) refuses to give Doherty the drug, saying it’s not yet safe for use outside the clinical trial, which Doherty was excluded from because of new cancer growth in his brain. That reason is simply not good enough for Doherty’s family and friends. If he will certainly die without the drug, why not let him try it? “They have an ethical responsibility to try to save a life,” his wife Rebecca Cumming said as she handed out “Help Save Darcy” stickers at the Ride to Conquer Cancer Sunday. “I think they’re afraid it will be harder to get the drug to market if the drug brings harm to patients like Darcy.” About 30 family friends were at the fundraiser to promote a change.org petition pressuring BMS to give Doherty access to the drug by Father’s Day. Wait much longer, Cumming said, and it will be too late. More than 171,000 have signed the plea. “We love our dad very much and we want a lot more time with him,” Doherty’s emotional 13-year-old son Ganden said in a video. A cancerous mole was first removed from Doherty’s back in 2003. By 2007 the cancer spread to his brain. He survived because of a then-experimental drug. His doctor said immune system off-switch blocker BMS-936558, which has had success in phase one of testing, could have similar benefits. BMS is aware of the petition, but did not budge on its decision. The company empathizes with patients who have limited treatment options, said spokeswoman Sonia Choi in a statement Sunday. Compassionate use requests are carefully reviewed using information from a patient’s physician, she said. To get access, the benefits must outweigh the risks. “At this time, there are not enough data on BMS-936558 to allow its use outside of a clinical trial.” Choi could not provide a timeframe on when more data might become available. The trial’s final stages are set for later this year or early 2013. “In the long term, the best way to ensure the broadest access for patients is to successfully register a medicine with health authorities through the conduct of well-controlled clinical trials.” “There’s no obligation on the drug companies to provide compassionate relief,” said Bernard Dickens, professor emeritus of health law and policy at the University of Toronto. BMS “can’t invest money in handing out unproven products if they’re not going to get data for study purposes.” But if the drug wasn’t safe enough to test on humans, it would not go to stage-two testing, argued advocate Frank Burroughs, founder of American organization the Abigail Alliance for Better Access to Developmental Drugs. For now, Doherty tires quickly. Sitting in his wheelchair at the fundraiser, the former big-bank financial services managing director called the petition an “amazing show of the human spirit.” He thinks it’s “kind of crazy” that he can’t get the drug. “It doesn’t hurt to give a guy a chance.” Source:http://www.thestar.com/news/article/1209218--dying-man-fights-to-get-experimental-drug-bristol-myers-squibb-won-t-give-him We have seen this type of action numerous times with BMS.They did this with Yervoy in the early days, closing compationate use. They appear to have no compassion or ethics, Just Greed!!!! to make a buck. I believe Bristol Myer Squibb is doing a disservice to the Cancer Community especially the Melanoma Patients.





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

There is no commitment to patients with stage IV Melanoma.

They have dollars Signs in the eyes and don't give a cr%& about the patients.

This is what Big Pharma has become. (Greed)

Take Care,

“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

Promising New Approach To Treating Cancer Means Hope For Many, But Remember This Is Just The Start Of The Journey..Melanoma ..Jim Breitfeller

Promising New Approach To Treating Cancer Means Hope For Many, But Remember This Is Just The Start Of The Journey

http://www.cancer.org/AboutUs/DrLensBlog/post/2012/06/02/Promising-New-Approach-To-Treating-Cancer-Means-Hope-For-Many-But-Remember-This-Is-Just-The-Start-Of-The-Journey.aspx






A while back , in 2011 I wrote about combinatorial therapy as the way to form a curative therapy for melanoma.See blog entry "“Schedule and Dose for Combination Therapy,”




It is now just starting to gain acceptance in the oncology world ASCO 2012. You need to block multiple pathways to shutdown the tumor's ability to side-step the immune system.If you search on my blog using the search field, you will be able to follow the science.

“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

 

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
 

Macrophage Activation… The Missing Link to Activation an immune response to Melanoma..Jim Breitfeller

"The development of Th1 cells producing high levels of IFN-gamma could not be induced with dendritic cells alone but required the addition of appropriately activated macrophages." Et al A. O'Gara March 23, 1993 "Dendritic cells and macrophages are required for Th1 development of CD4+ T cells from αβ TCR transgenic mice: IL-12 substitution f.or macrophages to stimulate IFN-γ production is IFN-γ-dependent"
Local IL-12 therapy stimulates Th cells to secrete Th1 cytokines. Exogenous IL-12 application creates an environment rich in IL-12 around the cancer site. In such a local environment, newly activated Th cells, responding to the presence of cancer, exit the blood and are influenced to become Th1 cells and secrete more Th1 cytokines and activate macrophages and NK cells. Activated macrophages will produce more IL-12 and via positive feedback, cell-mediated immunity can be promoted to battle the cancer thereby leading to the prevention of reoccurrence. As you can see, the activated macrophage secretes IL-12, IL-1a, IL-1b, and IL-6 along with a Chemoattractant, IP-10. Without macrophage activation, the immune response does not take place and the patient will relapse.(see graphic below)

With IL-1b and IL-6 missing, the T-Regulatory Cells (Tregs) rule the Tumor's Microenviroment. IL-6 controls Th17 immunity by inhibiting the conversion of naive CD4+ T cells into Foxp3+ regulatory T cells. IL-1β–Mediated Signals Preferentially Drive Conversion of Regulatory T Cells but Not Conventional T Cells into IL-17–Producing Cells (Danger Signal).So if the IL-1b signaling is missing,conversion of the Tregs never take place along with no Danger Signals.

Dr. Steven Rosenberg is using engineered T-cells that secrete IL-12 to stimulate Th cells to secrete Th1 cytokines. This sets in motion the positive feed back loop needed to initiate an immune response. His therapy is show great promise. “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 Dr. Jim Allison. ..The making of Yervoy..Melanoma..Jim Breitfeller

To Cure cancer, your immune system  must make memory cells that can distingush Melanoma cancer when and if you relapse. This done in at initial stage of T-cell Differentation and propagation. You must have the right Melieu (An environment or a setting) in place. This can be done with Systematic 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

Thinking outside the Box for the Elderly Melanoma Cancer Patients..Jim Breitfeller

Immunotherapy and Cancer - KTVN Channel 2 - Reno Tahoe News Weather, Video -
New rules of engagement for older patients The body’s immune system does weaken with age, but it also changes, and that changes the rules for fighting disease within the body. Dr. Curiel’s group started by examining an immune therapy that they previously had shown to work in younger hosts, including cancer patients. It’s designed to eliminate regulatory T cells (called Tregs), which are cells that turn off immune responses, allowing cancer to progress. Tregs increase in cancer. In young hosts, the drug turns off Treg activity, allowing the immune system to function better. In older hosts, even though the drug turns off the Tregs, it has no clinical benefit. Dr. Curiel asked the question why, and in this paper his team explains the answer. In older mice, when the drug turned off the Tregs, the researchers found that another type of immune suppressor cell (a myeloid-derived suppressor cell or MDSC) exploded in number to take the Tregs’ place, hampering clinical efficacy. That did not happen in young mice. The team added a second drug that targets the MDSC, and found that with those tools to help immunity, the older hosts can combat cancer just as well as the younger hosts. Adding the second drug afforded no clinical benefit to young hosts, as their MDSC numbers had not increased. “We’ve shown that an aged immune system can combat cancer just as well as a young one if you remove the impediments to successful immunity, which are different than those in younger hosts,” Dr. Curiel said. “We’ve shown that if you test all your immune therapy just in young mice and young people, you’ll never learn how it works in older patients — the ones most at risk for cancer. You might conclude that drugs don’t work in aged hosts, when they do. But they have to be combined with some help.” Human trials on the horizon The next step is to test these concepts in an immune therapy clinical trial for elderly patients, which the research team plans to do, Dr. Curiel said. The drug that is added is anti–Gr-1 antibody and would have to get approval from the FDA, meaning Clinical Trial. With that said, What if we added 5-Fluorouracil to immunotherapy like Yervoy and or Anti-PD1. 5FU immunogenic effects are primarily attributable to MDSC depletion. 5-Fluorouracil selectively kills Tumor-Associated Myeloid-Derived Suppressor Cells Resulting in Enhanced T Cell–Dependent Antitumor Immunity. This would be the one, two punch for elderly cancer patients. Let's Think outside the box. Myeloid-derived suppressor cells (MDSC) have been identified as a population of immature myeloid cells with the ability to suppress T-cell activation in humans and mice. These cells accumulate in the blood, lymph nodes, bone marrow, and at tumor sites in many human cancers and animal tumor models, and inhibit both adaptive and innate immunit. They notably have the capacity to inhibit CD8+ T cell antigen-specific reactivity by different mechanisms, mainly through their capacities to produce nitric oxide and radical oxygen species.




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

Is this the smoking gun to Melanoma and the reoccurrence the plasticity of the Macrophages?..Jim Breitfeller

Is this the smoking gun to Melanoma and the reoccurrence the plasticity of the Macrophages? The (TAM) Tumor Associated Macrophage or more precisely M2-Like Phenotype.
In my search for answers, I have been focusing in on how the tumor escapes detection by the immune system. We need to know what is going on in vivo during the different stages of melanoma.

The tumor mass is undoubtedly a multifaceted show, where different cell types, including neoplastic cells, fibroblasts, endothelial, and immune-competent cells, interact with one another continuously. Macrophages represent up to 50% of the tumor mass, and they certainly operate as fundamental actors. Macrophages constitute an extremely heterogeneous population; they originate from blood monocytes, which differentiate into distinct macrophage types, schematically identified as M1 (or classically activated) and M2 (or alternatively activated).

It is now generally accepted that TAMs have an M2 phenotype and show mostly pro-tumoral functions, promoting tumor cell survival, proliferation, and dissemination. High levels of TAM are often, although not always, correlated with a bad prognosis, and recent studies have also highlighted a link between their abundance and the process of metastasis.

In a recent 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.

Immunohistologic Characteristics of Tumor Infiltrating Immune Cells


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? We need to push the differentiation of the macrophages towards the M1 phenotype.

Macrophages are important tumor-infiltrating cells and play pivotal roles in tumor growth and metastasis. Macrophages participate in immune responses to tumors in a polarized manner: classic M1 macrophages produce interleukin (IL) 12 to promote tumoricidal responses, whereas M2 macrophages and M2-Like produce IL10 and help tumor progression. The mechanisms governing macrophage polarization are unclear but in 1990 it was discovered treatment of M2 macrophages with GM-CSF or IFN-gamma led to production of M1 phenotypic markers upon LPS stimulation. It also has been seen that if you block the IL-10 receptor with an antibody along with LPS (TLR4 agonist) stimulation or CpG (TLR9 agonist) stimulation you shift the Macrophage plasticity towards the M1 phenotype.

So what causes the high Macrophage (M2) to migrate towards the Tumor and its microenvironment? Does the tumor somehow recruit these (TAMs) Tumor Associated Macrophages? What are the characteristics of the M2 phenotype?

Hallmarks of M2 macrophages are IL-10high IL-12low IL-1rahigh IL-1 decoyRhigh production, CCL17 and CCL22 secretion, high expression of mannose, scavenger and galactose-type receptors, poor antigen-presenting capability and wound-healing promotion.

CCL17 and CCL22 chemokines within tumor microenvironment are related to infiltration of regulatory T cells in Macrophage 2 in melanoma. Early Detection of Tumor Cells by Innate Immune Cells leads to Treg Recruitment through CCL22 Production by Tumor Cells and Tumor Assocated Marophages (TAMs). It has been suggested that at early times during tumorigenesis, the detection of tumor cells by innate effectors (monocytes and NK cells) imposes a selection for CCL22 secretion that recruits Treg to evade this early antitumor immune response. The activated T-cells upregulate the CTLA-4 and PD-1. PD-1 ligation induces IL-10 production by monocytes, which together with PD-1 inhibits CD4+ T cell responses/activation. This is way for the immune system to use a checkpoint so that immune response does not lead to an autoimmune response. These receptors keeps the immune system in check.

Now in another paper I found this:


If you look at the above micrographs, you will see that the two patients that had relapsed (10710 and 10737) had IL-1b and IL-6 and TNF alpha missing. The macrophages were not activated!!!! The "Danger Signal" known as inflammation was missing! The non-responders most likely had their macrophages polarized to a M2-like phenotype by the Tregs and or IL-10.



So if the Macrophages are M2-like in the Tumor’s microenviroment, then if we control the Tregs, the upregulation of the of CTLA-4, PD-1 on the T-cells including the Tregs, and control the IL-10 production through anti-IL-10 antibody on the macrophages, we can shift the M2-like Macrophages into the M1 thus producing IL-12 shifting the differentiation of the Niave CD4+ T-cell the TH1 phenotype to activate the T-cells.


This all can be done with Yervor, Anti-PD-1 and Anti-IL-10 receptor antibody. You can get the tomor to shed antigentic protein by either whole radiation, Chemotherapy (TMZ- + Patrin-2) or Heat Shock.


CpG oligonucleotides induced NF-_B activation through the triggering of TLR9 signaling in TAM (Fig. 2), and the co-use of an IL-10 receptor Ab reduced IL-10 signaling in TAM, thereby reducing their M2 polarization.



Plasticity of Macrophage Function during Tumor Progression: Regulation by Distinct Molecular Mechanisms
Source: http://www.jimmunol.org/content/180/4/2011.full.pdf

HMGB1 from the dying tumors (irradiation, Chemotherapy, Heat Shock) will act as the Danger signal and bind to the TLR4 and activating the Macrophage (M1) and secrete IL-12 which acts upon the naïve CD4 T helper cells to differentiate to the Th1 phenotype.



petoh et al. has revealed an interesting role of TLR signalling in cancer therapy. They studied the immune-stimulatory properties of dying tumour cells after chemotherapy or radiation therapy. Using TLR4 and MyD88-deficient DCs, they show that TLR4 signaling is required for crosspresentation of antigens from apoptotic tumour cells on MHC class I to generate antitumour cytotoxic T cell (CTL) responses. Apetoh et al.also identified a “danger signal” from dying tumour cells, the nuclear protein highmobility group box 1 protein (HMGB1, see Figure) that triggers this protective immune response through activation of TLR4. According to their work, the interaction of high mobility group box 1 protein (HMGB1) released from dying tumour cells with Toll-like receptor 4 (TLR4) on dendritic cells is required for the crosspresentation of tumour antigens and the promotion of tumour specific cytotoxic T-cell responses.

So to sum it up, If you take Yervoy + Anti-PD1 + Anti-IL-10 along with radiation/Chemo could we get the right T-cell activation and Immune Response?

My guess you will activate the TLR4 pathway and induce the RIGHT IMMUNE RESPONSE.




So can we Get the Oncologists on board to propose and setup a clinical trial?
Time will only tell.
Remember the this blog. It will lead to 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