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

Pearls of Wisdom: Melanoma ..Jim Breitfeller

Pearls of Wisdom: Melanoma
Reviewed by Douglas Johnson, MD and Jeffrey Sosman, MD

This entry was posted on Tuesday, January 8, 2013 at 6:33 pm Management of Advanced Disease


Metastatic melanoma historically has had a very poor prognosis with a median survival of 6-9 months. However, recent advances in molecularly targeted therapy as well as immune based therapies have provided several effective treatment options for oncologists and their patients. In 2012 there are several important issues to consider in the management of patients with newly diagnosed advanced melanoma.


Advanced Stage III/Stage IV resectable disease

• In patients with advanced stage III disease or oligometastatic disease, consultation with an experienced surgical oncologist is warranted, as patients can experience long term survival with an aggressive surgical approach. Despite the advances in systemic therapy, surgical resection is still our preferred option in most of these clinical situations. One series of 64 patients showed a >30% four year survival in patients who had completely resected metastatic disease.1

•Another option we have offered is a short course of systemic therapy for 6-12 months prior to surgery with the intent to improve the chance that rapid recurrence of disease does not occur and to define the tumor’s responsiveness to the treatment.
•Patients should be considered for clinical trials in the adjuvant setting. Studies are ongoing to assess whether ipilimumab or vemurafenib is effective in preventing recurrences in high risk patients. For stage IV (M1) disease after complete surgical treatment there is no standard of care adjuvant treatment.


•Interferon, the current standard of care for fully resected stage IIb-III disease, is also an option in the adjuvant setting.
Molecular Testing

•All patients with metastatic disease should undergo testing for BRAF V600 mutations given the availability of targeted therapy for this mutation. This should include testing for the alternate V600 mutations that make up about 20% of BRAF mutations at this codon and appear sensitive to the BRAF inhibitors such as vemurafenib and dabrafenib.2 Patients with advanced local or regional disease can also be considered for testing since there are a number of clinical trials either recently or soon to be activated with BRAF inhibitor based therapy in BRAF V600 mutated melanoma at stage IIC-IIIC. Additionally, results will be available on progression so that therapy can be rapidly initiated if needed.
•Evaluation of several KIT mutations should also be considered in at least specific clinically defined subsets of patients. Though KIT mutations are present in only ~2% of all melanomas, acral (feet and hands) and mucosal melanomas harbor KIT mutations in 15-20% of cases. KIT mutations are sensitive to imatinib in about 25% of the cases based on limited numbers of patients.3
•NRAS mutations are also present in 15-20% of patients and though no targeted therapies are yet established as standard for this subset, there are a number of studies underway specifically targeting this mutation. Furthermore, the NRAS mutation may confer a poor prognosis to the melanoma.4


Standard therapies for metastatic disease

Vemurafenib
Vemurafenib is a BRAF inhibitor approved for patients with metastatic melanoma with BRAF V600 mutations (40-50%). In phase III trial data, objective tumor shrinkage was seen in well over 50% of patients, and clinical benefit seen in nearly all patients during the initial few weeks of administration. Median progression-free survival was 6.9 months (compared to 1.6 months with dacarbazine).5 Some important points regarding vemurafenib therapy:
•Responses are often rapid and dramatic. If patients with mutated BRAF V600 melanoma are highly symptomatic, vemurafenib would be our first line therapy in nearly all such patients.
•Patients will inevitably progress or relapse, often within the first year. Strategies to prevent or delay resistance are being pursued. In fact, recently the addition of a MEK inhibitor, trametinib, demonstrated an ability to improve the frequency of objective responses and the duration of progression-free survival in those melanoma patients receiving dabrafenib (BRAF inhibitor).
•Vemurafenib has clinical activity in patients with brain metastases in small series. Prospective phase II trials are pending completion. Trials with dabrafenib have also demonstrated frequent clinical benefits in such patients.6
•Secondary squamous cell carcinomas are common in BRAF inhibitor trials (10-25%).7 Suspicious lesions should be biopsied. Additionally, secondary melanomas and CMML have been reported in the presence of vemurafenib; almost certainly the drug has played a role to accelerate the appearance and growth of these tumors.
Ipilimumab (Yervoy)


Ipilimumab is an antibody to CTLA-4 and functions as an immune checkpoint inhibitor. This “removes the brakes” on the immune system which decreases immune tolerance to the tumor but may also cause autoimmune toxicities. In phase III trials, overall survival was increased compared to a vaccine in previously treated patients (10 mos vs. 6.4 mos), and in combination with dacarbazine compared with dacarbazine alone in the first line setting (11.2 vs. 9.1 months).8,9 Some important points to consider:
•Tumor burden on exam or on imaging may transiently worsen even in patients destined to respond. We do not repeat imaging until after 12 weeks of therapy unless the patient develops concerning new or progressive symptoms.
•Since even responding patients may have tumor growth or slow shrinkage, we are hesitant to use this therapy in highly symptomatic patients, especially if there are reasonable alternatives.
•Autoimmune side effects may be severe. Colitis, hepatitis, dermatitis, neuropathy, and endocrinopathies are the most common toxicities.
•Patients should be monitored closely for colitis. Concerning symptoms (diarrhea, melena/hematochezia, abdominal pain) require rapid evaluation. Though Imodium is appropriate for mild diarrhea (grade I), grade II toxicities or worse require prompt initiation of steroids. Colonoscopy should be performed to confirm the diagnosis in patients with severe colitis. Bowel perforation and death have been reported in extreme cases almost always when initial therapy is delayed.
•Headaches, with or without vision changes and fatigue may represent hypophysitis. Evaluation of TSH, cortisol, and testosterone, and brain MRI can aid in this diagnosis.
•We monitor TSH, cortisol, and liver enzymes at every visit.

•Other rare immune mediated side effects such as Guillan Barre syndrome, myasthenia gravis, sarcoidosis, and hemophilia have also been described.
Interleukin-2 (IL-2)


IL-2 has been used for many years in treating metastatic melanoma. It is associated with 6% durable remission rate (cures) and 15-20% overall response rate.10 Its use is limited to centers familiar with the associated severe side effects. Some points to consider when treating or referring patients:


•Therapy is limited to healthy patients usually under 70 years of age with adequate cardiac, pulmonary, renal, hepatic, and hematopoietic organ function and well controlled brain metastases. Nearly all patients experience treatment associated hypotension, multi-organ dysfunction, and vascular leak syndrome

•Though newer agents exist, IL-2 has the most long term data showing durable remissions in the minority of patients. We still consider this therapy in interested, eligible patients.
•Advantages of using IL-2 compared to ipilimumab include longer duration of use and more rapid assessments of benefit (8 weeks vs. 12+ weeks). Advantages to ipilimumab include outpatient use, generally less severe side effects, and possibly higher rates of durable remissions.



Cytotoxic chemotherapy

•Dacarbazine, temazolamide, and carboplatin/paclitaxel occasionally benefit patients with metastatic disease.
•No consistent survival benefit has been demonstrated with cytotoxic chemotherapy. Response rates are typically in the 5-10% range.
•We use chemotherapy only in patients who are not eligible for other therapies.
Which therapy should be chosen as first line therapy in patients with BRAF V600E/K mutations?
•This decision should be individualized. No head to head comparisons have been done with immunotherapy in the form of ipilimumab or interleukin-2 therapy. BRAF inhibitors are associated with high response rates but inevitable progression, while immune therapies have low objective response rates but durable remissions in a minority of patients.

•In patients with rapidly progressive or highly symptomatic disease, we typically use vemurafenib. In patients with asymptomatic disease, we favor immune based therapies for interested patients. An intergroup randomized cross over trial will address this issue, where half the patients start with vemurafenib and the other half on ipilimumab.



Promising Therapies


Therapy for metastatic melanoma is rapidly evolving. Many clinical trials are ongoing, and patients should be encouraged to participate in clinical trials for first line therapy or at progression if treated with standard therapy options. Some therapies that are likely to be approved are listed below.
•BRAF/MEK inhibitor combination therapies: Dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor) have both shown benefit individually over dacarbazine in phase III trials in patients with BRAF mutant metastatic melanoma. However, interest lies especially in combination therapy to delay resistance and disease progression. In a randomized phase II trial, combination therapy was associated with an improved objective response rate (54% vs 76%) and progression free survival compared to dabrafenib alone (9.4mo vs. 5.8mo).11 Additionally, the incidence of squamous cell carcinomas was dramatically decreased with combination therapy. Trials are ongoing comparing this combination with vemurafenib in untreated patients with BRAF mutations. An additional trial is evaluating vemurafenib in combination with GDC-0973, a MEK inhibitor.



•Anti-PD-1 therapy:

Several newer checkpoint inhibitors block the interaction between PD-1 (expressed on T-cells) and PD-L1 (expressed on tumor) which activates the immune system, hopefully in a tumor specific manner. A phase I trial with nivolumab (anti-PD1 BMS) data shows a 31% response rate with fewer autoimmune side effects than ipilimumab.12 Pneumonitis was described in several patients. Trials are ongoing in patients who have progressed on ipilimumab. Early reports of another anti-PD1, MK-3475 also show a remarkable response rate in patients either following Ipilimumab or de novo in the 40-50% response range.

•Anti-PD-1 + Yervoy therapy:

By using both Checkpoint inhibitors, you and block two pathways that the melanoma can't use for immunosuppression. This allows the activated T-cells to go unchecked and keeps the immune response switch on. This clinical trial is ongoing at Sloan Kettering, and Yale. Rumor has it that they are seeing high response rates.



References

1.

Sosman JA, Moon J, Tuthill RJ, et al. A phase 2 trial of complete resection for stage IV melanoma: Results of Southwest Oncology Group Clinical Trial S9430. Cancer 2011.
2.

Lovly CM, Dahlman KB, Fohn LE, et al. Routine multiplex mutational profiling of melanomas enables enrollment in genotype-driven therapeutic trials. PloS one 2012;7:e35309.
3.

Carvajal RD, Antonescu CR, Wolchok JD, et al. KIT as a therapeutic target in metastatic melanoma. JAMA : the journal of the American Medical Association 2011;305:2327-34.
4.

Devitt B, Liu W, Salemi R, et al. Clinical outcome and pathological features associated with NRAS mutation in cutaneous melanoma. Pigment cell & melanoma research 2011;24:666-72.


5.

Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. The New England journal of medicine 2011;364:2507-16.     “It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”
~Charles Darwin~
 Take Care,
Jimmy B

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

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

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

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

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

Jimmy B

 

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

Dr. Gomella,

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

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

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

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

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

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


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

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


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

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

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

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


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

1) You need to generate tumor-associated Antigens


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

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

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

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

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

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


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

 ~Charles Darwin~

Take Care,

Jimmy B

Legislation for Combinatorial Therapy >> Melanoma ..Jim Breitfeller

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

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

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

You and Your Doctor—Tackling Your Cancer Together

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

 Educate yourself


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

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

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

Ask questions and be proactive.

It’s your health—and your life!

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


Here are some questions you might ask your doctor:

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

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

~Charles Darwin~

Take Care,
Jimmy B

 

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

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

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

What I am trying tell is that by optimizing your personal therapy, you can extend your survival. “It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.” ~Charles Darwin~ Take Care, Jimmy B

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

 

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

 

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

Redirecting the Melanoma Tumor’s Microenvironment in Favor of the Activation of T-cells..Jim Breitfeller

Studies show that regulatory T (Treg) cells play a detrimental role in cancer immunotherapy because these cells accumulate in the tumor microenvironment and suppress immune responses. Moreover, Researchers recently showed the presence of tumor-specific CD4+, CD8+, and γδ Treg cells in several types of tumors, suggesting that they can induce antigen-specific, local immune tolerance at tumor sites. Tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MSC) could also play an important role in inhibiting immune responses and chronic inflammation, which has been linked to cancer development and progression. Both tumor-associated macrophages/DCs and MSCs promote tumor growth either by secreting immunosuppressive cytokines, including interleukin 10 (IL-10), transforming growth factor-β (TGF-β), and IL-1β, or by inducing Treg cell differentiation. More importantly, tumor cells have been shown to express inhibitory factors (IL-10, TGF-β, GAL-3, and IDO) to alter T-cell function. Immunosuppressive factors, such as FasL and TGF-β expressed by tumor cells, may directly inhibit tumor-reactive T-cell expansion or induce T-cell apoptosis. A recent studies suggest that tumor-associated galectin-1(Gal-1) and or Gal-3, a membes of the animal lectin family, contributes to tumor immune escapes by inhibiting the function of tumor-reactive T cells. Therefore, tumor cells constantly modulate T-cell responses by presenting tumor antigens and secreting immunoregulatory cytokines. Understanding the interplay between tumor cells and immune cells in the tumor microenvironment is essential for the development of effective cancer immunotherapy.

Researchers tested whether Gal-3 could activate other tumor-reactive or antigen-experienced T cells. Five melanoma-reactive T-cell lines, one prostate cancer–derived T-cell line, and two breast cancer–derived T-cell lines were selected and cocultured with 293 cells expressing Gal-3 for 12 to 16 h. they found that Gal-3–expressing 293 cells activated all of these T-cell lines to secrete IFN-γ but failed to activate naive CD4+ and CD8+ T cells purified from peripheral blood mononuclear cells (PBMC) of healthy donors . Suggesting that naive T-cell activation requires a strong T-cell receptor (TCR)-mediated activation, whereas tumor-reactive T cells can be readily activated by Gal-3. They also evaluated the cytokine profiles of CT28 T cells on Gal-3 stimulation. Gal-3 induced a high level of IFN-γ, granulocyte macrophage colony-stimulating factor, and low to middle levels of IL-4, which is similar to cytokine production induced by anti-CD3 (OKT3) stimulation. This is an indication that the Gal-3 complexes with the TCR synapse causing impaired signaling. Gal-3 binds and activates tumor-reactive T cells through carbohydrate-specific interaction.

Galectin-3 (GAL-3) localize mainly in Tumor cells, macrophages, epithelial cells,
Fibroblasts , and activated T-cells. Although galectin-1 has been shown to induce T-cell apoptosis, galectin-3 has conversely been shown to prevent cell death induced by Fas ligation. Galectin-3 has been shown to rescue cells from apoptosis by protecting against alterations of the mitochondrial membrane and formation of reactive oxygen species. A growing body of evidence supports the involvement of galectin-3 in tumor growth and metastasis.

Galectin-3 and IL-10 receptor needs to be inhibited to break the rest of the tolerance so the immunotherapy can have a greater effect with a better response rate.

Radiation + Yervoy + Anti-PD-1 + Anti-IL-10 receptor + GAL-3 Inhibitor= Robust immune response





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

~Charles Darwin~
Take Care,
Jimmy B

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