How therapy can teach your own immune system to fight cancer..Melanoma. Jim Breitfeller

How therapy can teach your own immune system to fight cancer

"The immune response to cancer
The immune system is our natural defense against disease. It destroys harmful bacteria and viruses that enter our bodies. In order to do this it has to recognize and label them as “foreign”. Once this happens, special types of cells in the immune system move in and destroy the invaders.

Our natural immune system can also detect cancer, because cancer cells are different from normal cells. In many cases, it will destroy these cancer cells before they turn into a detectable cancer.

Helping the immune system fight cancer
Sometimes our immune response to cancer fails and the cancer continues to grow. This can happen when cancer cells are not recognized by the immune system, or develop ways to cheat the system and escape detection. As a result, our immune system mistakes them for healthy cells and does not react.
Cancer immunotherapy aims to teach our natural defenses to identify cancer cells correctly – and then kill them.

ASCI*: a new approach that targets cancer antigens
ASCI* (Antigen-Specific Cancer Immunotherapeutics) is a new type of immunotherapy in development that targets cancer antigens and potentially destroys the cancer cells that bear these antigens. Cancer antigens are substances found on the surface of cancer cells, and are recognized as “foreign” by the body’s immune system.

ASCI* uses our own immune system to attack cancer. It does this by educating our immune system to identify and attack antigens displayed on cancer cells.
The immune system reacts towards the antigen in ASCI* – a reaction called immune response – and then attacks the cancer cells where this antigen is found."
Source:GlaxoSmithKline
http://www.immunotherapyforcancer.info/melanoma/index.shtml

There is only one major problem. Each melanoma patient has his or her own set of antigens based on their own tumors. Reseachers are trying to discover what are the major antigens that Melanoma patients exibit. For instance, MAGE-A3. There are literally thousands to choose from.

What if you get your body to produce them for you from your tumors. It sounds hard to believe but, radiation, chemotherapy with Dacarbazine plus (Patrin-2) Lomeguatrib and oblimersen sodium may help shed the right antigenic peptides. You have to get the right antigen to be presented on the dendritic cells acting as Antigen Presenting Cells (APCs) in order for the immune response to the cancer. The concentration of the antigen plays a major role in the intensity of the response.

Another problem is that you have to deplete or Block the suppressive function of the Tregs cells. This can be accomplished by lymphodepletion by preconditioning with cyclophosphamide and fludarabine or Anti-CTLA-4 blockade.

The final step of this process is the addition of interleukin-2 to activate and maintain the function of the CD8 + T-cells that mature into Cytotoxic T Lymphocytes (CTL’s). Dosing schedule and concentration of the drugs also play major role in weather an immune response is generated.



The Making of an Immune Response by Combinatorial Therapy Using Anti-CTLA-4 Blockade and Interleukin-2




"Mike Weber was kind to forward your paper and email. It appears that you have a very good sense of, and interest in, the immune response to melanoma and to cancer in general. I believe you are right that timing of the various components of the immune response, especially with combination therapies, is important, just as it is in the orchestration of a beautiful symphony."


~ Dr. Craig Slingluff ~



Melanoma and the Magic Bullet (Monoclonal Antibodies)







Take Care,
Jimmy B

Faltering Cancer Trials Melanoma.. Jim Breitfeller

Faltering Cancer Trials
Editorial
Published: April 24, 2010


The government’s system for judging the clinical effectiveness of cancer treatments, recently found to be in “a state of crisis,” must be repaired.

Here is a recent article from the New York Times. Thanks to Ed a carepage friend and colleage for bringing this to my attention.


Source:http://www.nytimes.com/2010/04/25/opinion/25sun1.html

Faltering Cancer Trials



We need the Patients to unite and get the best therapy for their condition. This is not rocket science, it is biochemistry at it's best. We need Big Pharma(Bristol Myer Sqiubb, Novartis,Pfizer, Plexikkon, Hoffman La Roche and others) to step up to the plate and do what is ethical. Not just looking at their bottom line. Without patients/consumers, these drug companies would not exist.

Our future survival is in our hands. The cure is out there. We need the medical community to take notice.




Take Care,
Jimmy B

Tregs Rule without Anti-CTLA-4 Blockade Melanoma..Jim Breitfeller

The Making of an Immune Response by Combinatorial Therapy Using Anti-CTLA-4 Blockade and Interleukin-2


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)

How Ipilimumab could work for You!! Melanoma.Jim Breitfeller

Pictures are from Bristol-Myer Squibb.

"If the timeline Fits, You must build it"

A Clinical Trial with this Protcol Design.


Take Care,

Jimmy B

There is No Magic Bullet to Cure Melanoma, And We Must Develop Multimodality Strategies..Melanoma..Jim Breitfeller

Expert opinion
“The research efforts directed towards the development of novel therapies for patients with metastatic melanoma have been intense despite disappointing clinical outcomes. It is clear that monotherapy for metastatic melanoma will not be successful, with every study to date yielding minimal clinical outcomes
data. Therefore, we must realize that there is no magic bullet to cure melanoma, and we must develop multimodality strategies to enhance the immune response to melanoma from different angles. This will require an unprecedented collaborative effort by many in order to overcome the historical competition between large pharmaceutical companies striving for ‘total cure’ with their drug.”

~ Dr.Adam I Riker~

We should realize that the future of drug development and design will depend heavily on the recent trend towards molecular medicine, and in particular, gene profiling efforts using gene microarray analysis. We are entering an entire new field of research dedicated to the molecular basis of cancer. Such research has the greatest potential to impact the way we treat patients with melanoma, focusing results on the prognostic significance of particular genes from a melanoma patient and basing clinical decisions as to whether such patients will (or will not) respond to a particular agent. The development of molecular signatures using gene microarray analysis has come to the forefront of existing research efforts identifying patients who may have an aggressive (versus indolent) form of melanoma and those patients with particular prognostic gene
signatures that may predict the response to forms of immunotherapy. The identification of such gene signatures has had important implications in the development of targeted immunotherapies for patients with metastatic disease. Thus, we must focus our efforts towards an improved understanding of the molecular and immunologic events involved in melanoma development and progression. We should also re-evaluate our present approach to immunotherapy and trial design, with many past trials failing to show clinical efficacy because of a lack of appropriate preclinical data that provide the essential rationale to perform such studies.

Source: http://www.southalabama.edu/mci/spf90/riker2.pdf

Immunotherapy of melanoma: a critical review of current concepts and future strategies








Take Care,

Jimmy B

Combinatorial Therapy, Will the Big Pharmaceutical Companies do what Is Ethically Right?Melanoma..Jim Breitfeller

Combinatorial Therapy, Will the Big Pharmaceutical Companies do what Is Ethically Right?




They include Plexikkon,Bristol-Myer Squibb, Pfizer, La Roche and Novartis.


I and other researchers have come to the conclusion that Combinatorial Therapy may be the only way to beat The BEAST, Melanoma



“A very obvious combination that we are trying to move forward now is PLX4032 with ipilimumab. There is unanimity among the academic researchers that this must be investigated. Both companies see the logic, but are reluctant with neither of their drugs yet being FDA approved. As you know ipilimumab (and tremelimumab) have not overwhelmed the FDA yet as they were told to show a response rate greater than 10% and neither drug could do so. Most melanoma researchers believe that there are additional patients who get real and long-term benefit without having their tumors shrink significantly in size, but the randomized trials are needed to show that. The worrying sign is the outcome of the tremelimumab randomized trial. So, now we are down to waiting for the results of the dacarbazine vs. dacarbazine plus ipilimumab phase III trial. If this is negative, we are in trouble as ipilimumab will have no clear path forward with the FDA. If it’s positive, then the idea of moving ahead with combinations becomes much, much easier. But, even it that trial is negative, we know that CTLA-4 blockade can induce phenomenal responses in some. So, in that case, we have to figure out (1) who those patients are and, (2) how to make those responses happen in more patients. The other way of thinking of #2 is that PLX4032 doesn’t work for as long as we would like and that making those responses more durable would be desirable.”


~ Dr. Keith Flaherty ~


“ Mike Weber was kind to forward your paper and email. It appears that you have a very good sense of, and interest in, the immune response to melanoma and to cancer in general. I believe you are right that timing of the various components of the immune response, especially with combination therapies, is important, just as it is in the orchestration of a beautiful symphony.”


~ Dr. Craig Slingluff ~



Dr Markovic,. I thought you might be interested in this combinatorial therapy

“We actually just submitted a paper to this affect in a small clinical trial where we used a conventional chemotherapeutic agent to induce a systemic anti-tumor immune response by simply timing drug delivery. And, it worked! It was a small study, so the data is only descriptive. I'm gearing up to move to a large trial right now.”


~Dr. Svetomir Markovic~



“To answer your last question first: Mutations in B-Raf and N-Ras have been shown to cluster at specific nucleotides. This strongly suggests that there is a cellular mechanism which targets these sites in each gene. However, you are probably right, that anti-CTLA4 and IL2 are working by enhancing immune surveillance of your melanoma.”


~Dr. Natalie Ahn~



“In conclusion, the combination of MART-1/DC with concomitant tremelimumab is feasible in patients with metastatic melanoma, especially when tremelimumab is administered every 3 months, and results in durable objective clinical responses at the higher range of the expected objective tumor response rates with either therapy alone. Therefore, this combination warrants further study in patients with advanced malignant melanoma.”

~Dr. Antoni Ribas~


The rationale for the CTLA-4 and IL-2 combination is once you activated the CD4+ Tcell and it crossprime the CD8+ Tcell , the IL-2 needed for the maintenance and functionality of the CD8+ T-cell.
If lymphocytes are cultured in the presence of Interleukin 2, it results in the development of effector cells which are cytotoxic to tumor cells.

“Fine theory but just theory that has never been tested in relevant clinical setting…”

~Dr. John M. Kirkwood~

"Glad to see your post on this series. From our perspective, the melanoma community isn’t waiting for a “miracle” to fall out of the sky to help patients. It’s clear that no single drug will likely effectively treat the disease; instead, a combination of drugs may be the answer. The Melanoma Research Foundation (MRF) is coordinating the Melanoma Breakthrough Consortium to accelerate research by bringing together leaders in drug development, laboratory and clinical research to find effective treatments. This collaboration will take years off the process. Patients with advanced melanoma have few or no treatment options and there’s no doubt in the urgency of moving forward to test new therapies today. More information is available at http://www.melanoma.org."

~Tim Turnham~
Executive Director
Melanoma Research Foundation




This is why we the patients need the Pharmaceutical companies to work together. Each therapy will not work alone as a single agent. The response rate is between 10 and 22 percent for each therapy. If you do a sequential treatment with the proper dosage and timing, you will see a synergistic outcome.

“There are three parts of the equation in a clinical trial. There’s who has control, who gets the reward, and who takes the risk. Patients take all the risk, they have no control, and they get no reward. Patients ought to be the ones driving the process and get the reward out of it and have the control, since they are the ones that take the risk.”


~Greg Simons~


If we are taking all the risk, shouldn’t we have a say in our Destiny?
“We need to all work together for the common good of the Melanoma Patients”
“We need to take greed out of the equation and just do what is ethically for humanity”

~Jimmy B~

Which elevator will you, The Pharmaceuticals Companies will Take?



Take Care,

Jimmy B

What If you combine Therapies? Response from Dr. Keith Flaherty..Melanoma ..Jim Breitfeller

What If you combine Therapies? Response from Dr. Keith Flaherty

Jim,


Thanks for the note.




"It is actually critical “patient advocates” which obviously includes patients, as well as those who are motivated to advocate on behalf of patients get involved in this process. One of the very reasons why I thought that a consortium was important to form, so that there could at least a body of researchers to point to as a group jointly focused on this direction. You see, companies find it very easy to say no to individual investigators when it comes to “difficult” requests. We need to make it harder for them when it involves losing time that our patients don’t have."



A very obvious combination that we are trying to move forward now is PLX4032 with ipilimumab. There is unanimity among the academic researchers that this must be investigated. Both companies see the logic, but are reluctant with neither of their drugs yet being FDA approved. As you know ipilimumab (and tremelimumab) have not overwhelmed the FDA yet as they were told to show a response rate greater than 10% and neither drug could do so. Most melanoma researchers believe that there are additional patients who get real and long-term benefit without having their tumors shrink significantly in size, but the randomized trials are needed to show that. The worrying sign is the outcome of the tremelimumab randomized trial. So, now we are down to waiting for the results of the dacarbazine vs. dacarbazine plus ipilimumab phase III trial. If this is negative, we are in trouble as ipilimumab will have no clear path forward with the FDA. If it’s positive, then the idea of moving ahead with combinations becomes much, much easier. But, even it that trial is negative, we know that CTLA-4 blockade can induce phenomenal responses in some. So, in that case, we have to figure out (1) who those patients are and, (2) how to make those responses happen in more patients. The other way of thinking of #2 is that PLX4032 doesn’t work for as long as we would like and that making those responses more durable would be desirable.

The companies need to hear it from patients and all patient-advocates that fairly obvious directions need to be pursued to find multiplicative effects. For the first time in melanoma, we have the building blocks in front of us and scientific rationale to guide us for the next steps.


Best regards, Keith

+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
Keith,


Base on my research, Ipi doesn’t work well is because it is lacking the tumor-specific antigens. DTIC+ Patrin-2, Irradiation, Oblimersen and others. We need the tumors to shed antigenic protein. To get the immune response into motion.


By using PLX-4032, my guess it will shed the protein needed. Then Anti-CTLA-4 Blockage comes in. It leaves the cd4+ T-cell activated and at the same time suppresses the Treg function allowing the CD8+ T-cells to get crossed primed and have them break though the tumor microenvironment. The HD IL-2 is added at the peak expansion of the CD8+ T-cells ( 50 days after Ipi is introduced into the host.). IL-2 is essential in the survival and function of the CTLs.


The above is my take on this combinatorial therapy. If you want, I can send you all the supporting papers of this theory.


Also, Can I get your permission to post your reply on my Blog?

Best Regards

Jim

+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++

What If you Combine three Therapies? PLX-4032 after remission, to let the tumor burden be low, Than add one dose of Anti-CTLA-4 Blockage. Wait 50 days so the CD8 T-cells would be at their maximum expansion. Then add two cycles of HD IL-2 to help grow and differentiate the CD8 T-cells into Cytotoxic T Lymphocytes (CTL's). You use the PLX-4032 to lower the tumor burden and shed the antigenic protein from the tumor.



For the patients that have the Braf mutation, use PLX-4032 to shed the antigenic protein and lower the tumor burden.

If you don't have the mutation, use radiation, chemo DTIC+ Patrin-2, Oblimersen and other small molecules to shed the antigenic protein.







Take Care,

Jimmy B

A note To Dr. Keith Flaherty.. Combinatorial Therapy..Melanoma..Jim Breitfeller..2-25-2010

"One year, Dr. Flaherty thought, when he heard the news. Certainly no triumph. But it was something. Something to be built on.

Novartis and Bristol-Myers had agreed to schedule teleconferences for later in the month to talk about combination trials. He checked the dates on his electronic calendar. A meeting with Pfizer was also pending."



Dr. Flaherty,

As early as May of 2009 I had come to the conclusion that the drug companies must work togther to come up with a stabilization/cure.

As a fellow researcher and Blogger, What can I do to help convince the pharma this it is in their best interest to work together. It would be a win, win for all, including the Patients like myself.

Keith, Please let me know what I can do to Help?

Best regards



Jim Breitfeller





Friday, May 8, 2009

There is Enough Room for Novartis, Bristol Meyer Squibb and Pfizer for each to take part in the Melanoma Space Melanoma.. Jim Breitfeller

There is Enough Room for Novartis, Bristol Meyer Squibb and Pfizer for each to take part in the Melanoma Space.

With ASCO Annual meeting coming up at the end of May, I believe that there will be some excitement around monoclonal antibodies. In particular, anti-CTLA-4 blockage treatment will be under the spotlight. What will the overall survival rates look like? Well, speaking from my experience, anti-CTLA-4 has prolonged my life for over 27 months where as a stage IV Patient, I was given 6 to 9 months. This could not have happen with out the extra help from Interleukin -2.

See, once the CD4+ T-cells activated, they need to grow and cross-prime the CD8+ T-cells. While activated T-cells secretes IL-2 at a certain concentration to help promote proliferation of the CD4+ T-cells. If there is too much IL-2 at the beginning of the immune response, I believe that the ratio of CD4/CD8/CD3 would be altered causing
the Tregs (CD4+ CD25 fox P3) to gain the upper hand of suppression of the immune response. A subset of CD4 + cells called CD4 + CD25 + regulatory T (Treg) cells that expresses Forkhead box P3 (Fox P3).

With just adding Anti-CTLA-4 first, It has been reported that it suppresses the T regs and pushes the balance towards an immune response. Once the immune response is in progress, the CD4+ T-cell is needed to co-stimulate the CD8+ T-cell. 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.

Once the CD8+ T-cell is activated, and is cultured in the presence of Interleukin 2, it results in the development of effector cells which are cytotoxic to tumor cells.

This is why we the patients need the Pharmacitical companies to work together. Each therapy will not work alone as a single agent. The response rate are between 10 and 22 percent for each therapy. If you do a sequential treatment with the proper dosage and timing, you will see a synergistic outcome.


“There are three parts of the equation in a clinical trial. There’s who has control, who gets the reward, and who takes the risk. Patients take all the risk, they have no control, and they get no reward. Patients ought to be the ones driving the process and get the reward out of it and have the control, since they are the ones that take the risk.”

~Greg Simons~


If we are taking all the risk, shouldn’t we have a say in our Destiny?

“We need to all work together for the common good of the Melanoma Patients”

“We need to take greed out of the equation and just do what is right for humanity”




Melanoma and The Magic Bullet (Monoclonal Antibodies)




Take Care,

Jimmy B

There is Enough Room for Novartis, Bristol Meyer Squibb and Pfizer for each to take part in the Melanoma Space Melanoma.. Jim Breitfeller

There is Enough Room for Novartis, Bristol Meyer Squibb and Pfizer for each to take part in the Melanoma Space.

With ASCO Annual meeting coming up at the end of May, I believe that there will be some excitement around monoclonal antibodies. In particular, anti-CTLA-4 blockage treatment will be under the spotlight. What will the overall survival rates look like? Well, speaking from my experience, anti-CTLA-4 has prolonged my life for over 27 months where as a stage IV Patient, I was given 6 to 9 months. This could not have happen with out the extra help from Interleukin -2.

See, once the CD4+ T-cells activated, they need to grow and cross-prime the CD8+ T-cells. While activated T-cells secretes IL-2 at a certain concentration to help promote proliferation of the CD4+ T-cells. If there is too much IL-2 at the beginning of the immune response, I believe that the ratio of CD4/CD8/CD3 would be altered causing
the Tregs (CD4+ CD25 fox P3) to gain the upper hand of suppression of the immune response. A subset of CD4 + cells called CD4 + CD25 + regulatory T (Treg) cells that expresses Forkhead box P3 (Fox P3).

With just adding Anti-CTLA-4 first, It has been reported that it suppresses the T regs and pushes the balance towards an immune response. Once the immune response is in progress, the CD4+ T-cell is needed to co-stimulate the CD8+ T-cell. 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.

Once the CD8+ T-cell is activated, and is cultured in the presence of Interleukin 2, it results in the development of effector cells which are cytotoxic to tumor cells.

This is why we the patients need the Pharmacitical companies to work together. Each therapy will not work alone as a single agent. The response rate are between 10 and 22 percent for each therapy. If you do a sequential treatment with the proper dosage and timing, you will see a synergistic outcome.


“There are three parts of the equation in a clinical trial. There’s who has control, who gets the reward, and who takes the risk. Patients take all the risk, they have no control, and they get no reward. Patients ought to be the ones driving the process and get the reward out of it and have the control, since they are the ones that take the risk.”

Greg Simons


If we are taking all the risk, shouldn’t we have a say in our Destiny?

“We need to all work together for the common good of the Melanoma Patients”

“We need to take greed out of the equation and just do what is right for humanity”


Take care

Jimmy B