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

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
 

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

Breaking Tolerance to Invoke an Immune Response to Cancer (Melanoma)..Jim Breitfeller

This post has been in the works for five years. It is with my tenacity and help from researchers around the world I am able to present this paper. It is still in draft form but I thought was important enough to just get it out there. It may be to technical for the average person/patient but, it is well worth downloading and presenting to your oncologist and or medical team.

The gist of the paper is we have responders and non-responders to therapy. WHY?? with the help of Four on the most influential reseachers in the Melanoma field, Dr. Craig Slingluff, Dr. Thomas Gajewski, Dr.Kingston Mills, Dr. Jim Allison and others, I was able to put some puzzle pieces together to tell a story. A story that may just save your life

In short, the non-responders may be/are missing the "Danger Signals" inflammatory Cytokines. Why, because their tumors are most likely harboring M2 phenotype macrophages (TAMs) Tumor assisted Macrophages.

But these TAMs have plasticity. This means they can change phenotype based on their miroenviroment. With some coaxing they can be change into M1 macrophages which in turn activate the T-cells. This means the patient needs to have therapies that promote M1 and Th1 cells. Well both Dr. Allison and Dr. Mills have discovered ways to do just that.

Please take some time to download and read this historic paper. It just may be the game changer for cancer.

Breaking Tolerance to Invoke an Immune Response to Cancer (Melanoma



I am going end with four slides.










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

~Charles Darwin~
Take Care,
Jimmy B

The Perfect Storm..Therapeutic use of Anti-CTLA-4 Blockage and IL-2 to enhance T-cell responses in vivo

The Perfect Storm..Therapeutic use of Anti-CTLA-4 Blockage and IL-2 to enhance T-cell responses in vivo
Dr. Cassian Yee
Fred Hutchinson Cancer Research Center
Clinical Research
Program in Immunology
Member Appointed: 2009
University of Washington School of Medicine Medicine

Oncology

Associate ProfessorAppointed: 2004
Fred Hutchinson Cancer Research Center
Immune Monitoring Laboratory
Director Appointed: 2003


In my studies, I contacted Dr. Cassian Yee about what I think would revolutionize Melanoma Treatment. Dr. Yee is noted for one of the first Scientists to harness the Immune system to fight Melanoma (2008).

"In what could be a breakthrough in cancer therapy, researchers report in The New England Journal of Medicine today that they succeeded in bolstering a patient's immune system enough to wipe out late-stage malignant tumors on its own. The scientists say the successful experiment could pave the way for new treatments of advanced cancer that spare patients the side effects of chemotherapy, which kills healthy as well as malignant cells."

Source: http://www.scientificamerican.com/article.cfm?id=patient-heal-thyself-body



Dear James,
i have not gone over in detail the information you sent, but i and think others will agree that anti-CTLA4 augments / lowers the threshold for a productive anti-tumor response once that is initiated in some form ('spark'). the role of aCTLA4 and Tregs is still not entirely worked out. I am glad that this has worked out well for you and with the emergence of immunotherapy in general as a treatment modality, with studies coming from Drs. Wolchok, Allison and others, we all hope that the
'Message keeps getting clearer'

Best
Cassian Yee


As you can see by the reply, I think we are onto something big.

I don’t want to waste your time but I think this issue is of the utmost importance. Your Ipilimumab is the major factor in keeping the CD4+ T-cells activated, but it can’t do it alone.



"You need the tumor specific antigens, (The Keys), you need the (Spark Plug) Anti-CTLA-4 and you need the (Gas) IL-2. Without these three key components your car won’t run." ~jimmy B~



As a patient/survivor/researcher of stage IV Melanoma I have scientifically accounted for why my therapy has worked. Above are supporting documents and also a paper (draft) I have written that describes my treatment journey. Please, take time out of you busy schedule and take a look these documents. Bristol Meyer Squibb holds a very promising drug, and when administered in the correct timing and dose, can jumpstart the (Car) The Immune system.

I think they are making great strides in the fight against Melanoma

We need to put it into practice.


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

~Charles Darwin~

Take Care,
Jimmy B

New drug can increase life for Melanoma patients..Ipilimumab..Jim Breitfeller

New drug can increase life for Melanoma patients
Source: Dr. Jay Adlersberg

NEW YORK (WABC) -- A new treatment can extend the life of patients with melanoma skin cancer, which has spread to other parts of the body.


The breakthrough treatment came from a lab. Bruce Shewmaker, who is 64 years old, and his family put their fate in the lab's hands. In 2000, Shewmaker found a malignant melanoma.

"It started with just a blemish on my foot that had been there for 10 years and & one day it changed," Shewmaker said.


The cancer was removed surgically and he had 6 good years. However, by 2006, the cancer returned and was found in his lungs. Chemotherapy and other treatments failed. Each failure was a blow to Shewmaker.

"It's hard to maintain your hope that you're going to get through this," he said.

Getting through late stage cancer was also the hope of Dr. Jim Allison of Memorial Sloan Kettering Center. He did experiments in mice with late stage melanoma, using a new untested drug. After some disappointments, one day he was startled.

"In one group of mice the tumors quit growing and it was a eureka moment for sure, it was very exciting," he said.

Dr. Allison's experiments led to a drug for humans called Ipilimumab, IPI for short.






“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

Phase 3 Clinical Study Of A New Cancer Immunotherapy Extends Survival In Patients With Refractory Melanoma..JimBreitfeller

The Cancer Research Institute, a nonprofit organization dedicated to the development of immune system-based treatments for cancer, announced its celebration of a significant new breakthrough in the treatment of melanoma, the deadliest form of skin cancer. The new treatment, a cancer immunotherapy created by Cancer Research Institute Scientific Advisory Council Associate Director James P. Allison, Ph.D., is designed to "take the brakes off the immune system," and is the first treatment ever proven to extend life for patients whose melanomas are unresponsive to existing cancer therapies.

Results from a large, randomized, multicenter phase 3 clinical study, published Saturday in the New England Journal of Medicine, confirm that the new treatment, a monoclonal antibody called ipilimumab, successfully boosts and sustains immune system responses against melanoma tumors in a large percentage of treated patients. The study also shows that the new treatment confers a survival advantage in a significant number of patients, resulting in durable protection against cancer.

According to the study report, 46 percent of patients on the trial who received ipilimumab were still alive at one year compared to 25 percent of patients on the trial who did not receive the new treatment. At two years, 22 to 24 percent of treated patients were still living compared to 14 percent in the study's control arm. The study tested ipilimumab alone, in combination with a vaccine targeting the melanoma tumor antigen peptide gp100, and vaccine alone.

"As an organization that for nearly 60 years has focused on advancing new immune system-based cancer treatments like the monoclonal antibody ipilimumab, the Cancer Research Institute considers this new breakthrough yet another significant success for the field of tumor immunotherapy and further validation that the immune system can be harnessed to treat, control, and prevent cancer," said CRI executive director Jill O'Donnell-Tormey, Ph.D.

In May this year the FDA approved the first therapeutic cancer vaccine, sipuleucel-T (Provenge®) for the treatment of prostate cancer. For the ipilimumab therapy, Bristol-Myers Squibb, the drug's manufacturer, says it expects to file for regulatory approval of its new treatment later this year. If successful, the drug could be the next cancer immunotherapy to receive FDA approval.

T cells (T lymphocytes) are immune cells the play a critical role in the body's attack against tumors. Ipilimumab represents the first in a new class of cancer immunotherapies called T-cell potentiators, which modulate the "stop/go" signals that control T-cell activation. By suppressing these "stop" signals, ipilimumab allows the T-cell response against cancer to proceed unimpeded.


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Ipilimumab specifically blocks CTLA-4, a molecule that inhibits the activity of T cells. Dr. Allison showed in 1995 that CTLA-4 was a negative regulator of T-cell responses, and hypothesized that blocking it could lead to strong tumor rejection. He went on to develop a monoclonal antibody that successfully blocks CTLA-4, and conducted the early mouse studies confirming his hypothesis of anti-CTLA-4-mediated tumor regression.

According to Dr. Allison, T-cell potentiation with ipilimumab may eventually help patients with many different types of cancer live longer. "Studies have shown that the immune system can recognize, target, and attack many different kinds of cancer," Allison said, "and ipilimumab may help to strengthen and sustain that immune response, no matter the type of cancer."

F. Stephen Hodi, M.D., a clinical researcher at the Dana-Farber Cancer Institute and principal investigator on the phase 3 study, said melanoma is just the beginning. "We can explore this new treatment in many other kinds of cancer, as well."

Smaller clinical studies of ipilimumab in other cancer types, including lung and prostate cancers, suggest the treatment has clinical activity, and further clinical research is ongoing to confirm these data.

According to Jedd D. Wolchok, M.D., Ph.D., also an associate director of the Cancer Research Institute Scientific Advisory Council, a CRI clinical investigator, and one of the clinicians involved in the large phase 3 study, there currently are no approved medicines indicated for patients whose melanomas return after primary treatment.

"The study is very significant," Wolchok stated, "as it is the first time ever that a randomized phase 3 study in melanoma has shown a new treatment to provide an overall survival benefit."

The landmark trial has other important implications for the field beyond establishing the effectiveness of this particular cancer immunotherapy. Axel Hoos, M.D., co-chairman of the executive committee of the CRI Cancer Immunotherapy Consortium, a program that seeks to optimize the development of the emerging field of immuno-oncology, and medical lead for ipilimumab at Bristol-Myers Squibb, said ipilimumab investigation represents a significant advance in how clinical studies of cancer immunotherapies are conducted and evaluated.

"The existing paradigm for evaluating the effectiveness of new cancer treatments is informed by experience with chemotherapy," Hoos said. "The chemotherapy paradigm does not entirely account for the biology and unique mechanisms of action of cancer immunotherapy."

To address this issue, the CRI Cancer Immunotherapy Consortium, in collaboration with international partner organizations, immunologists, and clinical oncologists around the world spearheaded the development of a new operating framework for immuno-oncology.

This new framework encompasses a clinical development paradigm that allows clinicians to more effectively investigate immunotherapies in clinical trials. According to Hoos, the ipilimumab trial results contribute to the validation of the new paradigm. "This offers a path forward for the field for more successful development of immunotherapies in the future," Hoos said.

The Cancer Research Institute is currently testing a variety of therapeutic cancer vaccines through its Cancer Vaccine Collaborative (CVC), a joint program with the Ludwig Institute for Cancer Research. Lloyd J. Old, M.D., director of the Cancer Vaccine Collaborative and director of the CRI Scientific Advisory Council, said the emergence of T-cell potentiators like ipilimumab as well as other modulators of immunosuppression has opened a new front for clinical discovery in cancer vaccine research.

"Over the past ten years, the Cancer Vaccine Collaborative has established an unprecedented understanding of the human immune system response to treatment with cancer vaccines," said Old. "There is now considerable evidence that the body recognizes cancer as foreign, but the full force of the immune system to combat cancer is blunted by inherent safeguards that have evolved over time to prevent the immune system from attacking healthy tissue, a condition called autoimmunity that can arise when these safeguard mechanisms fail. Blocking CTLA-4 with ipilimumab removes this constraint and permits more efficient immune control of the tumor."

According to Old, the introduction of ipilimumab and therapies that target other mechanisms involved in immune suppression launches a new era in the development of effective cancer vaccines, offering powerful new tools for overcoming the body's powerful restraints on generating protective cancer immunity.

"Ipilimumab represents a major step in the century old dream of incorporating the immune system in our battle against cancer," said Old, "and learning how to maximize the combined therapeutic effects of ipilimumab with other cancer therapies, including the new targeted therapies, is the immediate challenge."

"Our ultimate goal," said O'Donnell-Tormey, "is to establish highly effective immunotherapies as part of the standard of care in the treatment of cancer. The recent FDA approval of Provenge and the striking data on ipilimumab show that significant progress is being made toward achieving this goal."

"Given these recent advances," said Old, "we can predict that therapies based on immunological principles are poised to revolutionize our understanding and treatment of human cancer. Exploiting the power of the immune system to combat cancer is now clearly within our reach."

About the Cancer Research Institute

The Cancer Research Institute (CRI) is the world's only non-profit organization dedicated exclusively to the support and coordination of scientific and clinical efforts that will lead to the immunological treatment, control, and prevention of cancer. Guided by a world-renowned Scientific Advisory Council that includes four Nobel Prize winners and twenty-nine members of the National Academy of Sciences, CRI supports leading-edge cancer research at top medical centers and universities throughout the world. The Cancer Research Institute is ushering in a new era of scientific progress, hastening the discovery of effective cancer vaccines and other immune-based therapies that are providing new hope to cancer patients.

The Cancer Research Institute has one of the lowest overhead expense ratios among non-profit organizations, with more than 85 percent of its resources going directly to the support of its science, medical, and research programs. CRI meets or exceeds all 20 standards of the Better Business Bureau Wise Giving Alliance, the most comprehensive U.S. charity evaluation service, and according to Charity Navigator exceeds or meets industry standards and performs as well as or better than most cancer charities. CRI has also received an 'A' grade for fiscal disclosure and efficiency from the American Institute of Philanthropy as well as top accolades from other charity watchdog organizations.

Source: Cancer Research Institute

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

~Charles Darwin~

Take Care,
Jimmy B

Future Directions in Targeted Therapy for Melanoma..Jim Breitfeller

Future Directions in Targeted Therapy for Melanoma

“Our improved understanding of the molecular pathways that underlie the progression of melanoma has revealed numerous potential therapeutic approaches. We now face the challenge of developing targeted therapies directed at signaling pathways that are activated through mutations. Single-agent therapy is unlikely to be markedly successful,so there is also a pressing need to evaluate combination therapies, both with multiple targeted therapies and with targeted therapies plus conventional chemotherapeutic agents. It is hoped that these approaches will result in effective treatment options for patients with metastatic melanoma.”

~Dr. Keith T. Flaherty~


The Complexity of the T cell

In the midst of many promising discoveries, it became apparent to Dr. Allison and other researchers working in the field that stimulation of T cell response was more complicated than originally thought. As Dr. Allison and others discovered, first the T cell uses a structure called the antigen receptor to recognize a foreign antigen in the system (created by infecting viruses or bacteria, or new antigens found in tumor cells). Using an automobile as an analogy, Dr. Allison likens this step to turning the key in the car's ignition. "The car is running, but it's not going anywhere."

Recognition is not enough. Dr. Allison explains: "A second signal is also required, which, in the car analogy, would be the foot on the gas pedal." This second signal occurs when a particular family of molecules called the B7 molecule engages a molecule known as CD28 found on the surface of the T cell. Only these molecules are capable of initiating T cell response.

The final part of the car analogy is the immune system's brake -- an immune-regulating molecule, whose function was discovered by Dr. Allison's lab, known as cytotoxic T lymphocyte-associated antigen-4 (CTLA-4). CTLA-4 inhibits activated T cells in the immune system, preventing them from attacking the body's own tissues

It is now well accepted that recognition of specific antigen by the TCR is not sufficient for activation but that a second antigen nonspecific "co-stimulatory" signal is required. We have demonstrated that this second signal is provided the co-stimulatory receptor CD28 upon recognition of its counter-receptors, members of the B7 family, on the antigen-presenting cell. CD28 engagement is required under most situations for IL-2 production and proliferation. The lack of a CD28-mediated co-stimulatory signal upon TCR engagement can result in the induction of a long-lived state of nonresponsiveness.

We have recently found that co-stimulation is more complex than previously thought. CTLA-4, a homolog of CD28, also binds members of the B7 family, and binds them with affinities much higher than CD28. A wealth of data accumulated in the past few years show that CTLA-4 is an important downregulator of T cell responses. We have proposed that CTLA-4 plays a critical role in both the initiation and termination of T cell responses. According to this view, T cell activation is a dynamic process that is determined by the strength of the TCR signal; the strength of co-stimulation provided by CD28; and the magnitude of inhibitory signals generated by CTLA-4.

We have also demonstrated that CTLA-4 blockade can be used in combination with other methods of immunopotentiation or even conventional chemotherapy to obtain rejection of resistant tumors. We are currently examining the cellular and molecular mechanisms of the anti-tumor effect. The strategies we have developed in the mouse are currently in clinical trials for evaluation of effectiveness in treatment of prostate cancer and melanoma

Source: Sloan-Kettering Institute

"I believe that we are on the verge of bringing the manipulation of immune responses into the mainstream of cancer therapy," Dr. Allison said. "Recent work in cancer biology has shown that the genetic instability that is inherent in cancer results in a large number of mutations in proteins that create new antigens that the body has never seen before and ought to be readily recognized as foreign by the immune system. If we can kill some tumor cells, either as a result of a vaccine or treatment with more-conventional therapies, using agents such as anti-CTLA-4 ought to result in induction of potent immunity to these new targets. Thus, I believe that it is not unreasonable to think of many of the new targeted therapies as immunosupportive, and to use them in conjunction with the new approaches to enhancing immune responses."

~Dr. James Allison~

We are on the Verge of Harnessing the Immune System to recognize Melanoma cells as foreign. How this plays out will depend on if the Pharmaceutical companies like Bristol-Myer Squibb, Novartis, Pfizer, Hoffman La Roche, Plexikkon and other come together as one, to fight this Monster of a disease. Time will only tell. We owe it to the Patients.






Take care

Jimmy B

Melanoma_Missionary


"Today might be the worst day of your life...but tomorrow could be the best. You just have to get there."
~Unknown~

http://www.box.net/shared/kjgr6dkztj

Melanoma and The Magic Bullet (Monoclonal Antibodies)

Now that Ipilimumab is coming availble, please consider combinatorial therapy..Melanoma..Jim Breitfeller

Now that Ipilimumab is coming availble, please consider combinatorial therapy



Melanoma and The Magic Bullet (Monoclonal Antibodies)





Dr. James Allison of the Ludwig Center for Cancer Immunotherapy at Memorial Sloan-Kettering Cancer Center in New York, New York, described his laboratory’s latest research into the mechanisms of immune checkpoint blockade in the treatment of cancer, and showed data from mouse and human studies that support the further investigation of immune checkpoint blockade therapy alone and in combination with other anti-cancer therapies.

Source:http://www.cancerresearch.org/Programs.aspx?id=2412


The mechanisms of immune checkpoint blockade in the treatment of cancer











Take Care,

Jimmy B

Tremelimumab Shows Low But Durable Response Rate in Advanced Melanoma..Jim Breitfeller

Tremelimumab shows low but durable response rate in advanced melanoma
FEBRUARY 18, 2010

"NEW YORK (Reuters Health) - In a phase II trial in patients with advanced refractory or relapsed melanoma, tremelimumab (CP-675,206) showed a 6.6% objective response rate, with these responses lasting more than six months, a multinational group of researchers report in the February 1 issue of Clinical Cancer Research."

Source:http://www.curetoday.com/index.cfm/fuseaction/news.showNewsArticle/id/13/news_id/2350

Tremelimumab shows low but durable response rate in advanced melanoma


As you can see, the response rate is low as a monothrapy, but if you can get the tumors to shed antigentic proteins by combining with chemotherapy, irradiation and other molecules to stop the repair of the tumor Cell DNA, then you have antigens to present on the the (APCs) Antigen Presenting Cells. Interluekin-2 can be added at the end of the T-cell expansion to help grow and maintain the (CTLs) Cytotoxic T Lymphocytes.





adapted from Henry Stewart Talks by Jim Allison



Take care

Jimmy B

Melanoma_Missionary


"Today might be the worst day of your life...but tomorrow could be the best. You just have to get there."
~Unknown~

What do we Know about with Checkpoint Blockade in Cancer Immunotherapy?Melanoma,,Jim Breitfeller

TOPICS COVERED IN CHECKPOINT BLOCKADE IN CANCER IMMUNOTHERAPY

Activation of naive T-cells | CD28 and CTLA-4 | Differential regulation of T-cell responses | Responding repertoire | Biological role of CTLA-4 | Tumor-specific immune responses | Treg activity | CTLA-4/GVax | Immunotherapies | Conventional therapies | Ipilumumab | Clinical studies: melanoma | Reversible immune mediated toxicity


Slides
1. Introduction
2. Checkpoint blockade In cancer immunotherapy
3. Two signals are required for naive T cells activation
4. Many molecules shape the immune response
5. Functional asymmetry of CD28 and CTLA-4
6. Integration of TCR and costimulatory signals
7. Localization of CD28/CTLA-4 in migrating T cells
8. The movement of CD28 and CTLA-4
9. Do B7-1 or/and B7-2 dimerize?
10. B7-1 may dimerizes,while B7-2 appear monomeric
11. CD28 and CTLA-4 signaling complexes
12. Signaling processes on the T cell - APC junction
13. The role of CD28 and CTLA-4 cytoplasmic tails
14. Effect of agonists' strength on CTLA-4 localization
15. CD28 and CTLA- 4 trafficking
16. Differential regulation of T cell responses
17. CTLA-4 preferentially inhibits the best-fit response
18. Models for biological role of CTLA-4
19. How does CTLA-4 broaden responding repertoire?
20. Biological role of CTLA-4
21. Effect of CTLA-4 blockade
22. Effect of anti-CTLA-4 on transplantable tumor
23. Anti-CTLA-4 and GM-CSF synergise
24. Side effects following rejection of B16 melanoma
25. Effect of anti-CTLA-4/GVax
26. CTLA-4 has a cell-autonomous activity
27. Effect of exposure to anti-CTLA-4 in vivo
28. Effect of exposure to anti-CTLA-4 in vitro
29. Anti-CTLA-4 does not block Treg activity in vitro
30. Anti-CTLA-4/GVax increases Teff/Treg ratio
31. Summary: effective combinations of anti-CTLA-4
32. Chimeric murine CTLA-4 transgene
33. Effect of anti-CTLA-4 on MC38 tumor growth
34. MDX-010 (Ipilumumab)
35. Clinical response to a single dose of Ipilumumab
36. MDX-010-05 study design
37. Trial results: complete responder - patient 11
38. Example: CTLA-4 blockade effects on tumors
39. Reversible immune mediated toxicity
40. MDX010-020: Pivotal Phase III Trial
41. Autologous GVAX followed by MDX-010
42. Trial results: melanoma patient 15
43. Ovarian GVAX and Anti-CTLA-4 Ab - single dose
44. Reduction in tumor nodules following MDX-010 Rx
45. "Lupus-like" rash in ovarian cancer
46. Ovarian GVAX and Anti-CTLA-4 Ab effects
47. Research contributors
48. GVAX immunotherapy and Ipilimumab for HRPC
49. Trial results: PSA curves at dose-level 3
50. Trial results: bone scan improvement in patient 8
51. Checkpoint blockade works
52. Many questions still to be answered
53. Acknowledgements
54. Current lab members
55. END

Checkpoint Blockade in Cancer Immunotherapy


http://hstalks.com/lib.php?t=HST47.1385_1_3&c=252


Take Care,

Jimmy B

Inherent Complexities in Melanoma Research..Jim Breitfeller

Inherent Complexities in Melanoma Research

NCI Conference Highlights Promising Advances in Immunotherapy
EASTMAN, PEGGY

Oncology Times:
25 October 2008 - Volume 30 - Issue 20 - p 32-35


Still challenging researchers and slowing progress in the field of cancer immunology and immunotherapy are the inherent complexities of immunity, said other speakers at the meeting.
Regulation of T-cell responses is a lot more complex than we had initially thought, noted James P. Allison, PhD, Director of the Ludwig Center of Cancer Immunotherapy and Chairman of the Immunology Program at Memorial Sloan-Kettering Cancer Center.


Dr. Allison said that one reason there have not been more successful clinical strategies to mobilize the immune system to attack cancer cells is that until recently not enough attention has been paid to the multiple inhibitory mechanisms that serve to shape the immune response and minimize harm to normal tissues.

These mechanisms, he said, are a collective obstacle that can frustrate generation of effective anti-tumor responses.
His research has shown that the prototype of these inhibitory pathways is CTLA4, which limits T-cell proliferation. We have shown that blockade of CTLA4 can greatly enhance anti-tumor responses in a number of experimental tumors in mice, he said, noting that the CTLA4 blocker ipilimumab is now being developed by Medarex, Inc., and Bristol-Myers Squibb.

The results of clinical trials in more than 3,500 patients [for ipilimumab] have demonstrated objective, durable responses in a subset of melanoma, renal, ovarian, and prostate cancer patients. Thus for the first time we have objective responders, which he called exciting.

James C. Yang, MD, Senior Investigator in NCI's Surgery Branch, said that one immunotherapy combination of special clinical interest is ipilimumab plus interleukin-2 (IL-2). Dr. Yang, who chaired a symposium session, noted that in a Phase I/II study of 36 melanoma patients who received dose-escalating ipilimumab with a high-dose bolus of IL-2, the overall response rate was 22%. Long-term follow-up shows that six of the eight responders achieved ongoing complete responses with durations all exceeding four years.


Anti-CTLA4 antibodies have also been tried with other cancers, said Dr. Yang. He added that to extend the role of anti-CTLA4 therapy to a broader array of cancers, it will likely be necessary to combine it with other immunological manipulations, a combination approach which will hopefully boost the host immune response to cancer.


Take Care,

Jimmy B

Here is what Anti-CTLA-4 blockage can do!!!! Melanoma..Jim Breitfeller

Source:FORBES.COM

On The Cover/Top Stories

Targeting Melanoma

Robert Langreth 10.15.07, 12:00 AM ET

A new arsenal of therapies is aimed at a widespread and lethal skin cancer.




"Until recently researchers had little clue what molecular changes drive melanoma's rapid growth. But that has changed in a flurry of basic biology findings. "In terms of understanding what makes melanoma tick, in the past five years there has been an utter revolution," says Keith Flaherty, a physician at the University of Pennsylvania.

In 2002 gene researchers in the U.K. discovered that two-thirds of melanomas have a mutation in a growth-promoting gene inside skin cells called BRAF. The mutation causes the BRAF protein to become stuck in the "on" position, so it constantly sends a signal to the nucleus that it is time to proliferate. BRAF blockers are now in early-stage human trials at Novartis and separately at Roche, which works with partner Plexxikon. AstraZeneca is in midstage trials with 180 melanoma patients for a drug that hits a related target called mitogen-activated protein kinase kinase. "Every company I know of is interested in this," says Plexxikon Chief Executive Peter Hirth.

Therapies that trick the immune system into attacking melanoma are further along. Such immune system boosters have the potential to treat many types of cancer, but melanoma is one of the prime initial targets because it is one of the few cancers known to go into spontaneous remission on its own, indicating a possible immune response at work. The immune system activator interleukin-2 helps 15% of advanced melanoma cases and cures a few, but it produces such devastating side effects that patients must be hospitalized.

Pfizer's drug tremelimumab and Bristol-Myers Squibb's ipilimumab are antibodies to a protein called CTLA-4 (cytotoxic T-lymphocyte antigen-4) that acts as an emergency brake to prevent killer T cells from attacking healthy tissue. The antibodies bind to the CTLA-4, found on a cell's surface, and shut off the brake. Killer T cells then attack the cancer cells. Both drugs are in final-stage trials on hundreds of melanoma patients.

Much credit for the concept goes to immunologist James Allison, now at Sloan-Kettering. In the mid-1990s he theorized that CTLA-4 might prevent the immune system from mounting an effective response against tumors. Others were skeptical. But Allison showed in 1996 that he could shrink tumors in mice by injecting them with antibodies to CTLA-4.

Both Pfizer and Medarex, a biotech firm in Princeton, N.J., subsequently produced human antibodies to CTLA-4 and began testing them in patients a few years later. In 2005 Bristol-Myers Squibb paid Medarex $50 million in cash plus up to $480 in payments contingent on the success of Medarex's antibody.

At a meeting of cancer specialists last June Bristol-Myers and Medarex reported their drug shrank tumors in 46, or 13%, of 356 melanoma patients. The Pfizer antibody shrank melanomas in 7 of 84 patients in a midstage trial. The success rates were modest, but cancer doctors say that some patients may have had delayed responses. In some people tumors started to regress months after they had been declared treatment failures, says Bristol-Myers Vice President Renzo Canetta.

UCLA's Ribas calls the response rates "very low" and cautions that the anti-CTLA-4 drugs are just a first step. But even if the drugs improve survival only minimally, they are likely to be approved, he says. Bristol-Myers and Medarex are expected to finish key trials this fall. RBC Capital Markets analyst Jason Kantor pegged the odds of disappointing results "relatively high" in a recent report and rated Medarex an underperform; if the response rate is under 10%, it would make near-term approval "iffy", he says. Side effects of the drugs can include inflammation of the colon, thyroid or pancreas, or other autoimmune problems.

One reason for the limited response rate may be that some patients' T cells do a poor job of recognizing melanoma. To improve this situation, researchers are combining new antimelanoma vaccines with anti-CTLA-4 drugs. The idea is that the vaccines will train T cells to spot cancer, while the antibody will make sure the T cells remain activated long enough to do their dirty work.

Sharon Belvin was one of the first to try such a combination therapy. In May 2004, just a week before her wedding, she had developed a melanoma metastasis in her left lung. Belvin was only 22. The tumor grew through her chest cavity underneath her collarbone. Various chemo drugs and interleukin-2 produced nerve damage and other nasty side effects and didn't solve the problem. By June 2005 she had tumors in both lungs and could barely breathe or walk. Then Wolchok put her in a trial testing ipilimumab with an experimental Medarex vaccine. After only four treatments the tumors started to melt away. They were gone by mid-2006. The Jamesville, N.C. resident has been off therapy for a year and is pregnant with her first child, a girl due Feb. 10 2008."




By the Numbers

59,940 annual cases of melanoma in the U.S.

8,110 annual deaths.

99% five-year survival rate, localized disease.

15% five-year survival rate, widespread disease.

Source: American Cancer Society



Take Care,

Jimmy B

The B7 Family and Cancer Therapy: Costimulation and Coinhibition..Melanoma..Jim Breitfeller

www.aacrjournals.org Clin Cancer Res 2007;5271 13(18) September 15, 2007

Authors: Xingxing Zang and James P. Allison

Abstract: "The activation and development of an adaptive immune response is initiated by the engagement of aT-cell antigen receptor by an antigenic peptide-MHCcom plex.The outcome of this engagement is determined by both positive and negative signals, costimulation and coinhibition, generated mainly by the interaction between the B7 family and their receptor CD28 family. The importance of costimulation and coinhibition of T cells in controlling immune responses is exploited by tumors as immune evasion pathways. Absence of the expression of costimulatory B7 molecules renders tumors invisible to the immune system, whereas enhanced expression of inhibitory B7 molecules protects them from effectiveTcell destruction. Therefore, the manipulation of these pathways is crucial for developing effective tumor immunotherapy.Translation of our basic knowledge of costimulation and coinhibitioninto early clinical trials has shown considerable promise."

Source:http://clincancerres.aacrjournals.org/cgi/reprint/13/18/5271.pdf

The B7 Family and Cancer Therapy: Costimulation and Coinhibition



If you do anything, Please read this paper!!!

Jimmy B

Letter to Dr. Rosenberg! 3-24-2009 Melanoma ..Jim Breitfeller

Dr.Rosenberg, 3/24/2009

Remember you asked for my help getting the word out about your 72% response rate:
“Our latest treatment has a 72% objective response rate with 36% complete responses.

We are currently recruiting patients for our latest trial.
Is there some way to post this “Call for Patients” on the web site?”

Steve Rosenberg

Well now I have a request for you. I have been data mining on the internet and have been able to piece together why my combination therapy worked.

Below is a graphical representation of what went on using time as the x axis.



I was inoculated with anti-CTLA-4 mAb at the dose of 15mg/kg. Recent advance in autoimmunity research reveals that the innate immune system is able to recognize self-targets and initiate inflammatory response in a similar way as with pathogens. This is what anti-CTLA-4 blockage has done. Accordingly, alterations in cell morphology are recognized by the innate immune system resulting in an acute inflammatory response (Carroll and Holers,2005).


As you can see the innate immune antibody response takes about two weeks. In my therapy The Inflammatory response happen in 15 days.

Pinpointing when T cell costimulatory receptor CTLA-4 Is Engaged. In my therapy, I am trying to follow what had transpired and to try to back the findings up with scientific facts. So, after the inoculation of the 15mg/Kg of Tremelimumab (from Pfizer) IgG2 what happened?

Based on scientific theory the Monoclonal antibody blocks the CTLA-4 receptor causing the T-cell to stay active. So If my body’s chemistry is right, when and how do we know if the CTLA-4 blockage is engaged?

Dr. James Allison and colleagues in the late 1990’s did some studies with mice. In the mouse model, the anti-CTLA-4 blockage caused an autoimmune response which was diabetes in the mice. Before I go any further, I must make a note of caution. That is not all immune responses in mice models crossover to the human model, but the models are usually a good predictor. So with that said, In the research paper “Pinpointing when the T-cell costimulatory receptor CTLA-4 must be engaged to dampen diabetogenic T-cells”, it took about 12 days to see a response to the Anti-CTLA-4 mAb.

Source: http://www.pnas.org/content/97/22/12204.full

So if we have the danger signal and the B7 receptor blocked, all we need now is the antigen and the TCR T cell receptor to be engaged.

“Three major events must occur to induce CD8+ T cell–mediated, tumor-protective immunity against syngeneic melanoma. First, the T-cell receptor must be triggered by a (or multiple) self antigen–derived peptide MHC class I complex (7–13). Therefore, this event depends entirely on appropriate antigen presentation, which is most efficiently provided by mature dendritic cells (14). Peripherally tolerant or “ignorant” self-reactive T-cell clones, once properly activated, may serve as tumor-specific effector T cells (15, 16). Second, simultaneously with T-cell receptor triggering, a distinct second costimulatory signal must be delivered, mediated by IL-2, B7-1, or B7-2, which engage IL-2 receptors and CD28 on the surface of the T cell, respectively (17). A source of these cofactors for effective CD8+ T-cell stimulation can be provided by CD4+ T cells that release critical amounts of IL-2, or by mature dendritic cells that display an increased level of B7-1/B7-2 costimulatory molecules on their cell surfaces.

Third, inflammatory cytokines, including IL-1, IL-6, IL-12, and IFN-γ provide a third signal that acts directly on T cells (18), referred to as the “danger signal” (19, 20). This signal was found to optimally activate TH1 differentiation and lead to clonal expansion of T cells (18).”

Source: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=300854



CD4+ T cells bind an epitope consisting of an antigen fragment lying in the groove of a class II histocompatibility molecule. CD4+ T cells are essential for both the cell-mediated and antibody-mediated branches of the immune system:

• cell-mediated immunity
These CD4+ cells bind to antigen presented by antigen-presenting cells (APCs) like phagocytic macrophages and dendritic cells. The T cells then release lymphokines that attract other cells to the area. The result is inflammation: the accumulation of cells and molecules that attempt to wall off and destroy the antigenic material (an abscess is one example, the rash following exposure to poison ivy is another).

• antibody-mediated immunity
These CD4+ cells, called helper T cells, bind to antigen presented by B cells. The result is the development of clones of plasma cells secreting antibodies against the antigenic material.


So now with all three signals in, place we have the ability for cross priming the CD8+ T cells and clonal expansion.


The CD4+ T cells involved with manifold functionality:
Help or hinder anti-tumor response
But if you inoculate the system with IL-2 too early, you have CD4+ T cell expansion, and with that the CD4 Tregs increase as well which will suppress the immune response.

The therapeutic use of IL-2 is associated with a preferential expansion of CD4 cells expressing CD25, the alpha chain of the IL-2 receptor.

Treg cells:
unique T cell lineage

• CD4+ CD25high FoxP3high phenotype
• high expression of activation markers include CD25 (IL2Rα), GITR, CTLA4
• crucial for the maintenance of peripheral self tolerance
• involved in suppression of anti-tumor T cell reactions
• Immunosuppression is associated with the CD4+, but not with the CD8+ T cell population
• transfer of CD4+ effector T cells alone in CD4-/- host confers auto-immunity
• maintenance and function of CD8+ T cells requires CD4+ T cells which produce IL-2

The therapeutic use of IL-2 for HIV patients was aroused by an article by Kovacs et al. that appeared in the New England Journal of Medicine. That paper described a sharp increase in CD4 counts with a concomitant stable number of CD8 cells in 25 patients treated with IL-2.
Kovacs, J., M. Baseler, R. Dewar, S. Vogel, R. Davey, J. Falloon, M. Polis, R. Walker, R. Stevens, N. Salzman, J. Metcalf, H. Masur, and H. C. Lane. 1995. Increases in CD4 T lymphocytes with intermittent courses of IL-2 in patients with HIV infection. N. Engl. J. Med. 332:567-575
http://cdli.highwire.org/cgi/content/full/8/4/671

Treg cells are overrepresented in tumor lesions (lung, melanoma) and
reduced survival with increased infiltration of Treg cells.
They can inhibit the function of tumor infiltrating T cells (TILs).

With that in mind, In 1988, a research paper came out authored by Dr. Kyogo Itoh , Platsoucas,and Balch entitled: “Autologous Tumor Specific Cytotoxic Lymphocytes in the Infiltrate of Human Metastatic Melanomas” Activation by Interleukin 2 and Autologous Tumor Cells, and Involvement of the T Cell Receptor.

In the report all twelve Metastatic Melanoma tumor cell suspensions activated by IL-2 , TILs were present to a large degree. This confirmed your theory earlier. The TIL cell count increased to a maximum propagation in about 43 days. Tumors cells that were cultured with the TILs and the IL-2 were complete killed off. Lysing appeared five days into the experiment. The cytotoxic activity lasted for at least 59 days. In the control, without IL-2, the TILs eventually die off leaving the tumors cells enacted.

Itoh, K; Platsoucas, CD; Balch, CM
Autologous Tumor Specific Cytotoxic Lymphocytes in the Infiltrate of Human Metastatic Melanomas Activation by Interleukin 2 and Autologous Tumor Cells, and Involvement of the T Cell Receptor [published J . Exp. MED. The Rockefeller University Press. 1988 Oct 1; Vol 168 October 1988 1419-1441

http://jem.rupress.org/cgi/reprint/168/4/1419.pdf

In the above paper, It documented how long it takes to get maximum propagation of the CD4+, CD8+ and CD3+ T-cells. So I overlaid that information on my therapy. CD4+ T-cells propagate first, so if you inoculate at the CD4+ T-cells, you will generate more CD4+ clones.

It just so happens that the Il-2 therapy was introduced at the maximum CD8+ T-cell growth curve The same with the CD3+ cells also.

If lymphocytes (CD8+ T-cells) are cultured in the presence of Interleukin 2, it results in the development of effector cells which are cytotoxic to tumor cells.

So it looks like timing plays a major factor in how the Immune response plays out. I n a paper called “Opposing Effects of IL-2 in Tumor Immunotherapy: Promoting CD8+ T cell Growth and Inducing Apoptosis”. It showed in mice that the addition of IL-2 on the 4th and 5th day instead of days 1 and 2 had a dramatic effect on the couse of the response.Instead of being gone by day 12, the response lasted through day 30th. This was an indication that the timing of the IL-2 incoluation plays a major role in sequence response and duration.

Opposing Effects of IL-2 in Tumor Immunotherapy: Promoting CD8 T Cell Growth and Inducing Apoptosis Protul Shrikant2 and Matthew F. Mescher3
Center for Immunology, Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455

http://www.jimmunol.org/cgi/content/full/169/4/1753

Also, Prolong therapy with Il-2 has been shown to may hinder the CD8+ T cells.

“The timing and extent of exposure to IL-2 can clearly have dramatic effects on whether or not it is efficacious in activating, or reactivating, tumor-specific CD8+ T cell responses, making it difficult to know how to use it clinically in an optimal manner. The recently developed ability to detect and characterize tumor-specific T cells in patients using peptide/class I MHC tetramers may help in optimizing IL-2 therapy (40, 41, 42, 43). It may be possible to monitor activation of the cells as therapy proceeds and to stop administering the IL-2 when activation has occurred but before extensive apoptosis has been induced. The results described here strongly suggest that examination of the clinical effects of very limited IL-2 exposure would be warranted in trials using strategies that attempt to activate tumor-specific CD8 T cell responses”


http://www.jimmunol.org/cgi/content/full/169/4/1753


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

Please review my theory and make any comments.


Also I am enclosing a comparison graph of the IL-2 and CTLA-4 that you and your colleagues tried compared to the therapy I went through.

Thanks for listen and I hope to hear from you soon.

Best Regards

Jimmy Breitfeller

Melanoma Missionary