MedImmune Inks Deal for Pfizer's Anticancer mAb Therapeutic..Melanoma .Jim Breitfeller

MedImmune inked an in-license agreement with Pfizer for tremelimumab, a mAb therapeutic for various types of cancer. Pfizer presented final toxicity results of a Phase I dose-escalation trial of tremelimumab in combination with gemcitabine in chemotherapy-naive patients with metastatic pancreatic cancer.

Under terms of the deal MedImmune will assume global development rights to tremelimumab. Pfizer retains rights to use the drug compound with specified types of combination therapies.

Pfizer previously signed over developments rights covering tremelimumab in melanoma to Debiopharm after the mAb failed in a Phase III melanoma trial. The interim analysis found that it would not offer any benefit over standard chemotherapy. Thus in April 2008, Pfizer was forced to halt the trial.

A full evaluation of the data revealed a biomarker that predicted patients who were more likely to respond, according to Pfizer. Debiopharm will be responsible for conducting a new Phase III study that leverages this marker to select patients with unresectable, stage IV melanoma. At the time of inking the deal with Debiopharm, Pfizer said it would retain all commercial rights.

Tremelimumab is a fully human mAb that binds to the protein CTLA-4, expressed on the surface of activated T lymphocytes. "Adding another immunotherapeutic approach to our oncology pipeline, one which may employ the immune system itself to fight cancer, exemplifies our continued commitment to embracing this new era of cancer care," says Bahija Jallal, Ph.D., MedImmune's evp, R&D.

MedImmune has seven clinical-stage mAb programs for cancer treatment. Phase I candidates bind to CEA and CD3, CD22, IGF, CD19, and Ang2. The Phase II candidate targets PDGFRα and is being tested in lung cancer and glioblastoma. The company believes that the platelet-derived growth factor receptor alpha (PDGFRα) pathway, with its potential role in regulating transformation as well as tumor microenvironment, progression, and metastasis, may be an important cancer target.

MEDI-575 is a fully human mAb to PDGFRα being tested in lung cancer. It has been shown to inhibit signaling from PDGFRα on cancer cells and supportive stroma. However, MEDI-575 reportedly does not inhibit PDGFRβ, the inhibition of which has been associated with significant clinical toxicities including extravascular fluid accumulation.

MEDI-575 is a fully human mAb to PDGFRα being evaluated as a treatment for glioblastoma multiforme. MEDI-575 has been shown to inhibit signaling from PDGFRα on cancer cells and supportive stroma but not PDGFRβ, MedImmune says


Bristol Myer Squibb will now be looking in the rearview mirror and seeing MedImmune in it. Down the road we may see the price of these anti-CTLA-4 antibodies go down.


Also MedImmune has an US Patent Application 20100028330 - METHODS OF UPMODULATING ADAPTIVE IMMUNE RESPONSE USING ANTI-PD1 ANTIBODIES.

This is becomming Very Intersesting!!!

A race for the CURE!!!!!




It is good to see some Competition.



“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 does Ipilimumab (Yervoy) work? Melanoma..Jim Breitfeller

Ipilimumab is anti-CTLA-4 monoclonal antibody.

Ipilimumab C6742H9972N1732O2004S40
immunoglobul has a calculated molecular formula of C6472H9972N1732O2004S40 and a molecular weight of 145.4 kDa.in G1, anti-(human CTLA-4 (antigen)) (human gamma1-chain), disulfide with human kappa-chain, dimer [CAS] immunoglobulin G1, anti-(human CTLA-4 (antigen)) (human g1-chain), disulfide with human k-chain, dimer [CAS]

Half Life = 15 days

Tremelimumab (from Pfizer) is an IgG2
Tremelimumab is a fully human cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) IgG2 monoclonal antibody, presumably manufactured using transformed mammalian cells. Tremelimumab is a dimer (composed of two chains) linked by a disulfide/sulfhydryl bond. Tremelimumab has a calculated molecular formula of C6500H9974N1726O2026S52 and a molecular weight of ~150 kDa

Half life= 21 days




In T-cell activation, the receptor, CTLA-4 is upregulated on about day 3.

The CTLA-4 complex can suppress the immune response.

CTLA-4 that interferes with Dendritic cell (DC) costimulation via reduced CD80/CD86, (B7-1-2) expression and CD25 (IL-2 receptor) to allow for Treg survival, activation, and effective competition for limited IL-2 during infection.

Ipilimumab (Yervoy) works by blocking the CTLA-4/ B7-1/2 complex, which allows the costimulation of the CD28// B7-1/2 complex to take place. This takes the brakes off the immune response allow the response to go unchecked.

Another thing Yervoy does is that it decreases the signaling of STAT5 with increasing concentrations. That is why the best overall concentration is 10mg/Kg.

Phosphorylation of STAT5 decreased significantly with increasing concentrations of tremelimumab/Ipilimumab in monocytes from five healthy donors and from three patients with melanoma. Overall, these data demonstrate that monocytes express mostly intracellular CTLA4 and that CTLA4 is biologically active in this cell subset since exposure to tremelimumab/ipilimumab induces changes in intracellular signaling molecules.
By decreasing the signaling of STAT5 during Cell differentiation, TH17 and TH1 cells are mostly produced.






“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

Helper T Cell (Th17) Guides Killer Cells to Melanoma Cancer..Jim Breitfeller

Cancer manages to suppress or elude the body's immune system to survive and grow. Scientists at The University of Texas M. D. Anderson Cancer Center show this week in the journal Immunity how the helper T cell Th17 awakens the immune system to attack cancer. Senior author Chen Dong discusses the findings and their potential application for patients.

Helper T Cell Guides Killer Cells to Cancer


An important mechanism by which Melanoma cancer avoids antitumor immunity is by recruiting regulatory T cells (Tregs) to the tumor microenvironment. Recent studies suggest that suppressor Tregs and effector Th17 cells share a common lineage and differentiate based on the presence of certain cytokines in the microenvironment. Because IL-6 in the presence of TGF-β has been shown to inhibit Treg development and induce Th17 cells, they hypothesized that altering the tumor cytokine environment could induce Th17 and reverse tumor-associated immune suppression.



CTLA-4–B7 Interaction on the activated T-cell suppresses Th17 Cell Differentiation.Using anti-CTLA4 blocking antibody (Ipilimumab or tremelimumab) increases Th17 cells in peripheral blood of patients with metastatic melanoma. The Th17 cells can then migrate to the tumor's microenviroment. This sends the Danger Signal in the form of pro-inflammatory cytokines including IL-17. This is the third signal that is needed in the initiating of an immune response.

One of the mechanisms proposed is that CTLA-4 inhibition of T cell activation is due to antagonism of CD28-mediated costimulation. Both CD28 and CTLA-4 share the ligands B7.1 (CD80) and B7.2 (CD86); however, the affinity of the CTLA-4:B7 interaction is 10 times higher than the affinity of the CD28:B7 interaction. Although studies using CD28-deficient mice have shown that negative signaling through CTLA-4 is independent of CD28 expression, it is plausible that CTLA-4 interacts with B7 and prevents its interaction with CD28.

It is possible that T-cell activation can’t start until the level of CTLA-4 is block or decreased.

In my own experience, I did not get any activation until tremelimumab was introduced

If you Block the CTLA-4 and B7 with Ipilimumab or tremelimumab It will also take the brakes off the immune system and shift it towards activation.




I hypothesized that Th17 cells induce Th1-type chemokines, and in turn recruit Th1-type effector T cells into tumor microenvironment.

Recent data supports the notion that Th17 cells induce Th1-type chemokines through IL-17 and IFN- , and in turn recruit Th1-type effector T cells and NK cells into tumor microenvironment.

Increased tumor-associated IL-17 predicts improved patient survival

Mechanistically, Th17 cell–derived IL-17 and IFN- synergistically induced the production of CXCL9 and CXCL10, and in turn promoted effector T-cell migration toward tumor. The levels of CXCL9 and CXCL10 were directly correlated with tumor-infiltrating CD8+ T cells and NK cells. The data suggest that Th17 cells may play a role in promoting effector T-cell and NK-cell tumor trafficking and retainment, and the polyfuctional cytokine profile (IFN- +IL-17+) of Th17 cells is essential for synergistically inducing Th1-type chemokines.

Source:http://bloodjournal.hematologylibrary.org/cgi/content/full/114/6/1141



“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

Perspectives on the Management of Metastatic Melanoma: The Expanding Role of Immunotherapy..Jim Breitfeller

Perspectives on the Management of Metastatic Melanoma: The Expanding Role of Immunotherapy CME
John M. Kirkwood, MD; Jedd Wolchok, MD, PhD; Vernon K. Sondak, MD

08/05/2010

Perspectives on the Management of Metastatic Melanoma: The Expanding Role of Immunotherapy





“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

Pittsburgh Trip (06/28/06) in detail:How my Melanoma Journey Began..Jim Breitfeller

Pittsburgh Trip (06/28/06) in detail:

We left Rochester 4:00 am and arrived in Pittsburgh about 9:00 am. It’s a 5 hour trip if there are no detours along the way and you have a lead foot. I was very anxious to find out what my four options were so we had a cup of coffee and a croissant at their café and then proceeded to the doctor’s office. It was now about 9:30 am and my appointment was for 10:00 am. You know me, I like to be early. My wife says I am always too early. We proceeded to check in, and they gave me the normal treatment. They took my height, weight and vital signs. But this time they make a big deal about my weight. I had loss 4 lbs. So she calls over another nurse to retake my weight again (SOP) standard operating procedure. It was still short 4 lbs. I am thinking great, I am finally getting my weight under control. So, I turned to the nurses and said, “If you gave out cookies, you would not have these problems.” From their point of view, if you lose weight the cancer is active. Meanwhile, I’m thinking to myself, “Of course I lost weight. I’ve been so nervous. . . And, I just drove 291 miles without my breakfast. And we did make a couple of stops along the way.

Anyway, within 15 minutes we were called into the exam room. I am thinking this is great. The temperature in the room must have been 55 degrees. I was told to strip down to my underwear and put on one of those gowns with the slit up the back. I’m thinking, if this is anything like the last visit, I will freeze to death before anyone sees me. So, I told my wife, “If within 30 minutes, no one shows up, I’m going to put my clothes back on.” She said to me, that she was so cold that she had to go to the bathroom. So here we are, I’m shivering and my wife is crossing her legs to hold it in. So we are sitting and waiting, sitting and freezing for about 20 minutes. I did put my shoes back on to keep my feet warm.

Finally, the physician assistant steps into the room and greets us with a big “Hello!!!! ” She proceeds to tell us a little bit about the options, but then stops abruptly. She said: “the doctor should fill you in with all the details.” She then takes a look at my back, and with her hand, finds the lumps and starts counting them. She said “Good they are all there.” I am thinking, where the hell would they go, maybe on vacation? Nahhhhhhhhhhhh!
Anyway, no new lumps to report. She leaves the room to get the doctor and my wife follows her to find the bathroom. Dee returns relieved, just in time here hear a knock at the door.

In walks Dr. Kirkwood who greets us with a big smile and a hand shake. He asks us if Melissa, the physician assistant, has filled us in with the option details and could we go over the details with him to make sure we understood them. My wife and I turned to each other and our faces must have looked white to him. We tried to regurgitate what little information she had shared, although, it was VERY brief and we had not taken any notes. Melissa had told us that the doctor was going to go over the details. Well, my quick thinking wife said that Melissa gave us a very, very brief overview and that at our last meeting with him, we got all of 5 minutes of his time. I guess Dr. Kirkwood did not realize that the last time he had talked to us was before he had the PET/CT scans results and the options were different.
Anyway, he began to draw us a flowchart of the options on the exam table paper. He was really getting into it.

He started with the options at the top, and continued with the first line, second line and third line of defense therapy. It looked like an ISO document. I could draw it for you, but you’d probably fall asleep reading it. The worse part is, you have to have the therapies done in a certain sequence or you can not move to the next line of defense. Another problem, you can not mix and or match. To make things even worse, one of the better lines of defense had to be removed because I have the wrong blood type for the vaccine therapies. I was hoping to use this as my third line of defense.

My wife and I just sat there staring at the flowchart for what seemed like hours. We both started to run different scenarios in our head. We came up with the same conclusion. We needed a therapy that would allow us to “work outside the box” and not “cuff my hands”. We wanted to have the Ticilimumab/ Tremelimumab (from Pfizer …anti-CTLA-4 therapy as my second line of defense. CTLA-4 seems to slow down the immune response, so blocking it with an anti-CTLA-4 antibody may make the immune response more active.

Soooooooooooo! I signed my life away for the phase I study of Patrin in combination with dacarbazine under our protocol 03-091, which is currently not a nationally available trial.


I also signed up to allow Tumor Biopsies. Hey why not. It is FREEEEEEEE!!!! And I get two tumors removed for the price of one. And they say nothing is free in the world anymore. They will remove one and study it before treatment, and then take another one out and see what effect the chemo had on it during the first cycle of therapy. You know me I am always looking for a bargain--and, I am always doing some sort of research.

That is it from my end to yours. That sounds gross. Anyway take care, and keep those messages coming.


If you want to follow my journey you can read it here or at Carepages.com with comments.

http://www.carepages.com/carepages/jimmyBreitfeller

We needed a therapy that would allow us to “work outside the box” and not “cuff my hands”. We wanted to have the Ticilimumab/Tremelimumab (from Pfizer …anti-CTLA-4 therapy) as my second line of defense. CTLA-4 seems to slow down the immune response, so blocking it with an anti-CTLA-4 antibody may make the immune response more active.

That was then, This is Now, NED!!!

"Think Outside the Box"


“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 Options in Melanoma Therapy Dr John Kirkwood Feb 2010..Jim Breitfeller

Take Care,

Jimmy B

Challenges and Opportunities Ahead..Melanoma Therapy ..Jim Breitfeller

"A dynamic picture is emerging in which the immune system is far from quiescent in cancer, and tumor cells elaborate a host of countermeasures to evade immune destruction. In essence, these are two systems which co-evolve over time. Clinical outcome is ultimately a balance between the proliferation of tumor cells and the immune response which attempts to control these cells. Various treatments may perturb these two systems in different ways - in good clinical outcomes, the immune response ultimately dominates, while in poor outcomes, tumor cells dominate.

It is becoming clear that the challenge in tumor immunotherapy lies not only in lack of tumor recognition, but also ineffectivity of the immune response that develops. While efforts to elicit tumor-specific T cells directly in patients via vaccination may overcome potential mechanisms of immune evasion by tumors cells, current immunotherapeutic strategies do not address their potential immunomodulatory mechanisms.

Understanding the molecular mechanisms which underlie T cell dysfunction in cancer will be important to devise novel adjunct strategies to enhance or modulate T cell responses after tumor-specific T cells have been elicited. It will likely take a multi-faceted approach acting at several steps along the T cell activation and effector activity pathway to finally achieve success in cancer immunotherapy."


The Laboratory of Peter P. Lee, MD at Stanford University

This multi-faceted approach acting at several steps along the T cell activation and effector activity pathway is what I call Combinatorial Therapy.

We first start at obtaining the Antigen to be presented on the Antigen Presenting Cell. Then once we think we got it, we need to proceed to the Activation step. Ipilimumab (Anti-CTLA-4 Blockade) helps to keep the activation in the on position. It also has a dual role, in keep the Treg's surpressive function out of play in the Tumor 's microenvirioment.
Interleukin -2 is the final step to complete response. It is the growth factor for the CTL's, which help maintain functionality and survival of the Cytotoxic T Lymphocytes (CTL's).






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

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~

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

antSent: Tuesday, January 05, 2010 10:42 AM
To: 'Rosenberg, Steven A. (NIH/NCI) [E]'
Subject: FW: The Perfect Storm: Therapeutic use of Anti-CTLA-4 Blockage and IL-2 to enhance T-cell responses in vivo

Dr. Rosenberg, I wanted you to know about this because your Research has allowed me to put this puzzle together. Thank you for sharing your research.

Thanks for communicating with me over these years. Some researchers like to hold their cards close to their chest. I would rather show my hand to help find a cure/stabilization.

I know in your Research clinical trials you are approaching 50% complete response for HLA-02 positive patients. What does that calculate out to if you include the other subtypes?

I am hoping that the information that I have pulled together will benefit the whole Melanoma community. I know that my therapy was not a one off data point and that is why I am pursuing this combination theory to the max.

Thanks for lending me your ear.

By obtaining the above papers, I now have real evidence of what took place with my therapy as a Melanoma patient and why it worked. The paper that I wrote called Melanoma and the Magic Bullet (Monoclonal antibodies) was right on track. I did a little bit of hand waving early on, but NOW I have the evidence that the IL-2 timing plays a critical roll in the outcome of the clinical trials.

Also, I am now certain that the Anti-CTLA-4 blockage (Ipiilimumab or what I used Tremelimumab was the spark that started it all. “You Can’t Start a Fire Without a Spark!!” For the Anti-CTLA-4 Blockage did three things:


1. It blocked the B7 receptor causing the activated CD4+ T-cells to stay activated for a longer period

2. It pushes the balance of the CD4+ T-cell differentiation towards the Th17 lineage or also known as the THi cells which stands for inflammatory Cells. They generated the third signal “Danger Signal” which is one of three needed to activate the CD8+ T-cells. This base on research that Dr. Ribas has done.

3. It suppresses the Treg expansion/function tilting the immune response balance towards activation instead of Anergy.


CTLA4 blockade increases Th17 cells in patients with metastatic melanoma Ribas


According to Dr. Wolchok and investigating the dose of Anti-CTLA-4 blockage recently, the higher the dose the better the immune response.

The best overall response rate was 11•1% (95% CI 4•9—20•7) for 10 mg/kg, 4•2% (0•9—11•7) for 3 mg/kg, and 0% (0•0—4•9) for 0•3 mg/kg (p=0•0015; trend test).

 10mg/Kg 11.1% response rate

 3mg/Kg 4.2 % response rate

 0.3mg/Kg 0% response rate

This data was base on Ipilimumab as a monotherapy

Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study




I did 15mg/Kg of Tremelimumab (one Dose) and got a COMEPLETE RESPONSE.

My guess is there is threshold that is needed to broken to tip the balance of tolerance to activation.


It all comes down to timing and the dose concentration.

Therapeutic use of IL-2 to enhance antiviral T-cell responses in vivo




IL-2 was giving in the contraction phase of the CD4+ T-cells and at the Maxiumum growth phase of the CD8+ T-cells. It is as I refer it as the “Perfect Storm”. This is all based on a paper by Dr. Itoh and colleagues in 1988.


Activation by Interleukin 2 and Autologous Tumor Cells, and Involvement of the T Cell Receptor




Dr. Heryln’s Paper “Tumors as elusive targets of T-cell-based active immunotherapy.
Tumors as elusive targets of T-cell-based active immunotherapy



It is going to be a great 2010!!!!!


Take Care,

Jimmy B

Am I seeing Double?? Melanoma..Jim Breitfeller

I was able to get in touch Dr.Bucay the Dermatologist that went through therapy. She gave me her timeslines so I graphed it.



I guess the main take away is "There is Hope". Two complete responses doesn't make a cure. We used two different monoclonal antibodies with two different regimens - (medicine) a systematic plan for therapy (often including diet). It is interesting to note that the time between therapies are very close.

The overall time difference my be due to the fact that we had different tumor loads.

My bet is on the timing!!!


Take Care,

Jimmy B

Medarex is Giving away the Company without it's Shareholders Consent at a Fireside Sale to Bristol-Meyer Squibb of 50 % off! Melanoma Jim Breitfeller

Headline Pfizer's melanoma disappointment compounds Medarex misery

Source EP Vantage

Company Medarex

Related: Bristol-Myers Squibb, Pfizer

Date April 02, 2008

The termination of a phase III trial of tremelimumab in melanoma, after interim data suggested the drug was no better than standard chemotherapy, could mean Pfizer has lost one its most promising pipeline products.
While the company is not abandoning the antibody, which is in trials for a range of solid tumours, the prognosis is not good, and is the last thing Pfizer needs as it attempts to drive through new products ahead of the looming loss of Lipitor. For Medarex, the news is an even bigger blow, because it makes potential future royalty payments look more uncertain, and adds to concerns around a similar antibody the biotechnology firm is developing with Bristol-Myers Squibb.
Tremelimumab, or CP-675,206, is an anti-CTLA4 antibody which targets a molecule found on the surface of T-cells, and has been shown to diminish the immune response to tumours. By using a human antibody to block the activity of CTLA-4, immune systems may attack tumours more strongly.
There are two anti-CTLA4 MAb’s under development, tremelimumab and ipilimumab, both in final stage trials for melanoma. The Pfizer drug was developed using technology similar to Medarex’s, hence the royalties due on future sales. The latter, also known as MDX-010, was developed by the biotechnology group, and is being progressed under the alliance with Bristol-Myers Squibb.
The consensus net present value of MDX-010 to Medarex is $1.23bn, according to EvaluatePharma’s NPV Analyzer, which represents just over a third of the total value of the group’s pipeline. CP-675,206 is valued at $547m, accounting for just under a fifth, meaning half of the company’s pipeline value is tied up in the success of anti-CTLA4 MAbs.
Medarex shares were trading 15% lower, at $7.88, in early trade.

Second most important

Pfizer shares also opened weaker, down 1%. The consensus NPV of the product is $2.29bn, representing 2% of the company’s share price. That makes it the second most important pipeline project, after axitinib.
Analysts had penciled in sales of $499m by 2012, and were anticipating launch this year. The product is phase II trials in non-small cell lung cancer, colorectal and breast cancers, among others.
Melanoma would be a big opportunity for both CP-675,206 and MDX-010, because the cancer represents a significant unmet medical need. The main drugs used to fight the disease are the interferon alphas, sales of which are in decline as newer, more effective products have been developed for other tumour types, with melanoma remaining hard to treat.
If the antibodies fail to make the grade, the indication will lose two its most promising looking new candidates.

Diminishing hopes

Hopes that the anti-CTLA4 MAbs would prove to be a significant new treatment options were lowered when Bristol-Myers and Medarex released mixed results from three registration phase III trials of ipilimumab in December. One study did not meet the primary endpoint, although the companies have stressed that response rates across the trials were positive.
MDX-010 is due to be filed with the FDA in the first half of the year, and Medarex has expressed confidence that the regulator will approve the drug on the data. Sales forecasts commence in 2008, given the fast track status the drug has been granted, but confidence in straight-off approval has diminished, with many analysts believing further trials will be required.
A sign that Bristol-Myers is also less than confident came in a December slide show given by the company, which showed sales of MDX-010 starting in 2010.
Consensus for 2012 sales sits at $389m recorded by Bristol-Myers. A key event for defining the potential of the drug will come when full data from the three phase III trials is presented at this year’s ASCO conference at the end of May.
With today’s set back, that presentation takes on even greater importance for the biotechnology group. Its shares fell 21% when the news on MDX-010 was announced in December, and aside from a recent small rally, have been falling since.
With the stock now trading at three-year lows, significant progress with the remainder of its pipeline is needed to restore confidence.

This content is written, edited and published by EP Vantage and is distributed by EvaluatePharma Ltd. All queries regarding the content should be directed to: news@epvantage.com
EP Vantage is a unique, forward-looking, news analysis service tailored to the needs of pharma and finance professionals. EP Vantage focuses on the events that will define the future of companies, products and therapy areas, with detailed financial analysis of events in real-time, including regulatory decisions, product approvals, licensing deals, patent decisions, M&A.
Drawing on EvaluatePharma, an industry-leading database of actual and forecast product sales and financials, EP Vantage gives readers the insight to make value-enhancing decisions.



Source: EvaluatePharma®
Source:
http://www.evaluatepharma.com/Universal/View.aspx?type=Entity&entityType=Product&lType=modData&id=10530&componentID=1002#&&_ViewArgs=%7b%22_EntityType%22%3a0%2c%22_Parameters%22%3a%7b%22_ContextData%22%3a%22%7b%5c%22isEPVantage%5c%22%3atrue%2c%5c%22percentage%5c%22%3a-1%2c%5c%22searchWords%5c%22%3a%5c%22%5c%22%2c%5c%22sectionID%5c%22%3a%5c%22%5c%22%2c%5c%22storyID%5c%22%3a%5c%22152431%5c%22%7d%22%7d%2c%22_Type%22%3a1%7d


Based on this information plus 1.5 bn for the othe 39 drugs in the pipeline plus 1.23 for mdx-010 and 2.29 for Tremelimumab, or CP-675,206 equals 5.02 bn

Lets do the math 2.4 bn/16per share = 5.02 bn/X X= 33.5 dollars per share

BMY got a half off deal.


Show us the $$$$$$$$$$$!!!!!!!!!!

Medarex List of products in the pipline!!!! 14-Aug-09 10:13 pm
Product Count
Medarex
Marketed 3
R&D 62
Suspended in R&D 1
Abandoned in R&D 42
Disposed in R&D 1
Total (Medarex) 109

DEPTH COMPETITIVE INTELLIGENCE AVAILABLE ON

Product Generic Name
Medarex
aB7H4
-
ADC Research Program
-
AFP-VAC
-
ALT-212
-
AMG 714
-
Amgen Antibody-1
-
Amgen Antibody-2
-
Amgen Antibody-3
-
Amgen Antibody-4
-
Amgen Antibody-5
-
Anti-bacterial MAb
-
Anti-CD70 MAb-MGBA conjugate
-
Anti-Cripto-1 MAb
-
Anti-CTLA-4 project
-
Anti-SDF-1 MAb
-
aPtk7
-
ARIUS/Medarex Cancer Research Project
-
AutoImmune MAb Collaboration
-
Avalon Cancer Antibody Collaboration
-
BMS-66513
-
Cancer antibody collaboration
-
Cancer MAb Project
-
Cancer Research Project
-
CDX-110
-
CDX-1307
-
CDX-1401
-
CDX-2101 (inc. Ribi-529 adjuvant)
hepatitis B vaccine

CDX-2301
anthrax vaccine

CDX-2401
-
CDX-2410
-
CDX-S03
-
CNTO 95
intetumumab

COL-VAC
-
Compugen antibody collaboration
-
CP-675,206
tremelimumab

DTS-201
-
Duocarmycin B2
-
Eos/Medarex/Biosite Cancer MAb
-
Euroscreen MAb collaboration
-
FG-3019
-
Fully-Human RSV MAbs
-
Graft versus Host Disease Project
-
GVHD-TOX
-
Haematological cancer MAb collaboration
-
HGS-TR2J
-
HuMax-CD4
zanolimumab

HuMax-Inflam (MDX-018)
-
IL-13 Antibody
-
Ilaris
canakinumab

IMC-18F1
-
IMC-3G3
-
Immunology MAb collaboration
-
Infectious Disease Research Project
-
Ipilimumab
ipilimumab

KW-2189
pibrozelesin

LOR-A04
-
Lung Cancer MAb
-
MAb Research Project
-
MAGE3
-
MDX 1097
-
MDX-060
iratumumab

MDX-066
-
MDX-067
-
MDX-070
-
MDX-11
-
MDX-1100
-
MDX-1105
-
MDX-1110
-
MDX-1185
-
MDX-1203
-
MDX-1204
-
MDX-1338
-
MDX-1342
-
MDX-1388
-
MDX-1401
-
MDX-1411
-
MDX-1414
-
MDX-214
-
MDX-22
-
MDX-220
-
MDX-240
-
MDX-33
-
MDX-44
-
MDX-447
-
MDX-RA
-
Medarex/Pfizer UltiMAb Antibody
-
Medarex/Raven MAb
-
MEDI-545
sifalimumab

MEDI-546
-
MelanA
-
MEL-VAC
-
NI-0401
-
Novartis Antibody 2
-
NY-ESO-1
-
OGeS cancer antibody collaboration
-
ONO-4538 / MDX-1106
-
Organon/Medarex MAb
-
Osidem
-
Ovarian Cancer MAb
-
PSA-VAC
-
Resiquimod (inc. CDX-1307 adjuvant)
-
SARS MAb
-
Second-generation MDX-070 toxin conjugate
-
Simponi
golimumab

Stelara
ustekinumab

Transcobalamin MAb
-
Valortim
-
VAP-1 Antibody Program
-
Vitamin B12 Receptor Blocking MAb

Take Care,

Jimmy B

Please give and show your Support..Melanoma..Jim Breitfeller

I am writing to you today for your help and support. As you know Melanoma therapy depends on cutting edge drugs. These drugs take years to go through the FDA process and most of them fail. This is what happen to Tremelimumab (from Pfizer) is an IgG2.
It was compared to the “gold standard” Dacarbazine as a single agent. The trial was setup to fail at the beginning. Pfizer wanted to go it alone instead of using the research that was published stating it would be better in combination of other therapies. This drug
saved my life.

We need organizations like the Abigail Allaince to help us in the quest to get these and other cutting edge drugs. Our lives depend on it. So won’t you please Donate today. If you have loveones that are fighting cancer, don’t you want them to have access to these cutting edge drugs?

Here is happen to one family “My husband fought Stage IV Mel for two years and one week... The last year was spent waiting for the Ipilimumab that never came...”

There are many stories like this.


Please give generously to this organization. You can use paypal on the website
Abigail Alliance website


Thanks for Caring

Jimmy B … Melanoma Missionary

Patient/Survivor of Stage IV Melanoma Cancer


Take Care,

Jimmy B

Blame it on the Tregs!!!! Melanoma.. Jim Breitfeller

As you Know I have been off line lately. I have been following up on some research that I have been doing and actually fired another letter to Dr. Rosenberg. It all has to do with Tregs (CD4+ CD25+ T-cells). They are Known for surpressing the immune response that we want. In Adoptive cell transfer done at the NCI, Rosenberg and colleagues do Lymphodepleting step before injecting the patient with (TILs) tumor-infiltrating lymphocytes. This is a systemic chemotherapy that transient elimination of host immune system includes:


suppressive cells
regulatory T (Treg) cells,
myeloid derived suppressor (MSC) cells,
Natural killer T cells (NKT) cells
cells competing for cytokines
transiently increased function of antigen presenting cells (APCs)

By doing this It gives the TILs a fighting chance of survival and activation. Il-2 is added for maintance and survival of the TILs.

So I came across a paper "CTLA-4 Blockade Confers Lymphocyte Resistance to Regulatory T-Cells in Advanced Melanoma: Surrogate Marker of Efficacy of Tremelimumab?"

Author by:
Cédric Ménard1,2, François Ghiringhelli1,4,5, Stephan Roux1,2, Nathalie Chaput1,2, Christine Mateus3, Ursula Grohmann6, Sophie Caillat-Zucman7, Laurence Zitvogel1,2 and Caroline Robert1,3

Authors' Affiliations: 1 Center of Clinical Investigations, CBT507, 2 Institut National de la Sante et de la Recherche Medicale U805, and 3 Department of Medicine, Dermatology Unit, Institut Gustave Roussy, Villejuif, France; 4 Department of Medicine, Centre Georges Francois Leclerc, 5 CRI Institut National de la Sante et de la Recherche Medicale 866, Faculté de Médecine, Dijon, France; 6 Department of Experimental Medicine, University of Perugia, Perugia, Italy; and 7 Institut National de la Sante et de la Recherche Medicale U561, Hôpital St. Vincent de Paul, Paris, France

Purpose: Anti–CTL antigen-4 (CTLA-4) monoclonal antibody (mAb) has led to encouraging antitumor activity associated with immune-related adverse events in patients with heavily pretreated melanoma. However, mechanisms of action and surrogate immunologic markers of efficacy have not been reported thus far.

Experimental Design: We monitored the immune responses of 10 melanoma patients included in a phase II clinical trial, which evaluated the efficacy of a second line of therapy of tremelimumab anti–CTLA-4 mAb in patients with metastatic melanoma. The frequency of blood leukocyte populations in association with T cell and regulatory T cell (Treg) functions were evaluated.

Results: Prior to therapy, patients with advanced melanoma presented with a severe CD4+ and CD8+ T cell lymphopenia associated with blunted T-cell proliferative capacities that could be assigned to Treg. Tremelimumab rapidly restored the effector and memory CD4+ and CD8+ T-cell pool and TCR-dependent T-cell proliferation that became entirely resistant to Treg-mediated suppression. Progression-free survival and overall survival was directly correlated with the acquisition of a biological response defined as the resistance of peripheral lymphocytes to Treg-inhibitory effects (obtained in 7 of 10 patients).

Conclusion: CTLA-4 blockade seems to be a valuable strategy to revive reactive memory T cells anergized in the context of stage IV melanoma, and our work suggests that memory T-cell resistance to Treg resulting from anti–CTLA-4 treatment might be a biological activity marker for tremelimumab in patients with melanoma.

I am the process of obtaining this Paper. I believe it holds another piece of the Melanoma puzzle.


Take Care

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

Pinpointing when T cell costimulatory receptor CTLA-4 is Engaged!!!! Melanoma..Jim Breitfeller

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

Pinpointing when the T-cell costimulatory receptor CTLA-4 must be engaged to dampen diabetogenic T-cells



Well in my therapy, an inflammatory response was noted on day 15. This suggests that the costimulatory receptor was fully engage to cause a inflammatory response, The “Danger Signal”

“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

Tremelimumab dose selected for further testing due to favorable Safety, Tumor Response in Melanoma ..JimBreitfeller

Posted February 25, 2009
Tremelimumab given at two dosing regimens afforded durable tumor responses in patients with metastatic melanoma, according to data from a phase-1/2 trial.

Researchers conducted a phase-1/2 trial to assess the safety of tremelimumab in multiple doses and to examine the efficacy of the agent and the appropriate dosing regimen.

To determine the recommended phase-2 dose, phase-1 IV infusions of tremelimumab at 3 mg/kg, 6 mg/kg or 10 mg/kg were given to 28 patients with metastatic melanoma for up to one year. During phase 2, 89 patients received tremelimumab 10 mg/kg once each month or 15 mg/kg every three months.

The researchers reported no dose-limiting toxicity during phase 1. Eighty-four patients were assessable for response during phase 2 at which time 10% reached objective antitumor responses; one complete response and three partial responses in each dosing regimen comprised the best overall objective response.

Most responses ranged from three to 30 or more months and the most common adverse events were diarrhea, rash and pruritus. Grade-3/4 adverse events had a frequency of 13% in the 15 mg/kg arm and 27% in the 10 mg/kg arm. Frequency of serious adverse events was 9% in the 15 mg/kg arm vs. 23% in the 10 mg/kg arm.

“Both phase-2 regimens generated durable tumor responses,” the researchers wrote. “Based on its more favorable safety profile, 15 mg/kg every three months was selected for further clinical testing.” – by Stacey L. Adams

J Clin Oncol. 2009;doi:10.1200/JCO.2008.19.2435

The phase-3 data from ASCO, in terms of survival, show that tremelimumab given at 15 mg/kg every three months is a bit better than for the control arm of dacarbazine (DTIC-Dome, Bayer Healthcare) or temozolomide (Temodar, Schering). But, the difference was not statistically significant; median survival was a month better, but this is less than we were looking for. So we must ask: What is the real difference between clinical responses to tremelimumab and dacarbazine? In the recently published study of Camacho et al reporting the phase-1/2 experience and the larger phase-2 multicenter study I presented to ESMO and ASCO in 2008, as well as in the phase-3 experience that Toni Ribas presented to ASCO, there are very profound differences between the type of responses seen with anti-CTLA4-blocking antibodies and with conventional chemotherapy. About 8% to 10% of patients with melanoma have objective response to this modality and the majority of these have a very durable response. For example, in the phase-2 trial results I reported to ASCO and ESMO, 15 of 16 patients who had objective response with tremelimumab response was durable past six months -a very different pattern than we see for dacarbazine and temozolomide. Tremelimumab and ipilimumab are active agents in a fraction that is roughly the same as interleukin-2, interferon-alfa, and dacarbazine or temozolomide. In the largest trial of temozolomide ever conducted - results recently presented at ESMO by Patel et al.- response rates were 10% for dacarbazine vs. 14.8% for temozolomide, but there was no difference in the overall survival or the progression-free interval between these regimens. Dacarbazine and temozolomide responses do not seem to confer survival benefit in part because these responses are rarely durable. The 10% of patients who responded to the anti-CTLA4-blocking antibodies exhibit characteristically and qualitatively different kinds of responses in metastatic stage-4 disease.

When looking at the difference between the phase-3 and phase-1/2 trials, the phase-1/2 results clearly show that for tremelimumab there are very durable, high-quality responses--and the same can be said for ipilimumab. But the problem is, when you conduct a conventional trial in advanced metastatic melanoma to look at median survival, the survival median provides a different readout than the readout of durable responses. The quality of responses to tremelimumab and ipilimumab are still worthy of pursuit. The fact that the phase-3 trial of tremelimumab shows a little better outcome than dacarbazine in terms of median survival does not reflect these high-quality responses that go out well past six months, and will take different follow-up to document. So that is what is going on now: the long-term follow-up of those patients to make a qualitative assessment of the kind of response that they exhibited is really what we need.

Looking at the data from the phase-3 presentation by Ribas, the one thing that may have weighed differentially in favor of tremelimumab in the forest plot of the data was higher lactate dehydrogenase (LDH). This is curious when you think about it. It may or may not be real, but if patients who have higher LDH (perhaps worse disease) benefit more from tremelimumab than from dacarbazine or temozolomide, the study was designed in a way that may have disfavored the anti-CTLA4-blocking antibody. The protocol excluded those people who had higher than twofold elevated LDH – so, by the design of the trial, curiously the outcome may have been slanted in favor of temozolomide or dacarbazine.

Finally, it remains to test the role of anti-CTLA4 blocking antibodies in the disease setting where we have found the greatest relative benefit for other immunotherapy, such as IFN alpha. The adjuvant exploration of anti-CTLA4 blocking antibodies may show even greater relative benefit and warrants phase-3 study in relationto IFN alpha.

– John Kirkwood, MD

Source:http://www.hemonctoday.com/article.aspx?rid=36459

Tremelimumab dose selected for further testing due to favorable safety, tumor response in melanoma


Jimmy B

Will the real Dosage of CTLA-4 Please stand up???Melanoma ..Jim Breitfeller

In tring to figure out why my therapy has worked so far, I came across a major discrepancy in dosage used compared to the clinical trial by Dr. Rosenberg. His maximum was 3.0 mg/Kg of CTLA-4 and I did 15 mg/Kg.

That is a 5 fold increase. I do know he used Ipilimumab and I used Tremelimumab (from Pfizer). They are both anti-CTLA-4. They both have a molecular weight of 145.4 kDa. and ~150 kDa respectively.

Half lives of 15 days and 21 days simular. So why the great Disparity in dosage. Could that be a flaw in the trial?


Tumor regression and autoimmunity in patients treated with cytotoxic T lymphocyte-associated antigen 4 blockade and interleukin 2: a phase I/II study.

Maker AV, Phan GQ, Attia P, Yang JC, Sherry RM, Topalian SL, Kammula US, Royal RE, Haworth LR, Levy C, Kleiner D, Mavroukakis SA, Yellin M, Rosenberg SA.

Surgery Branch, National Cancer Institute, National Institutes of Health, CRC Room 3-3940, 10 Center Drive, MSC 1201, Bethesda, MD 20814, USA.

BACKGROUND: Cytotoxic T lymphocyte-associated antigen (CTLA)-4 can inhibit T-cell responses and is involved in tolerance against self antigens. We previously reported autoimmune manifestations and objective cancer regressions in patients with metastatic melanoma treated with CTLA-4 blockade. The possibility of activating tumor-reactive T cells while removing inhibitory activity with CTLA-4 blockade has stimulated interest in using anti-CTLA-4 antibodies in combination with other cancer immunotherapies to improve clinical outcomes. In this study, we assessed the antitumor activity and autoimmune toxicity of CTLA-4 blockade in combination with an immune-activating stimulus, interleukin (IL)-2, in patients with metastatic melanoma.

METHODS: Thirty-six patients received anti-CTLA-4 antibody every 3 weeks. Three patients per cohort received doses of .1, .3, 1.0, and 2.0 mg/kg. Twenty-four patients received 3.0 mg/kg. All patients received IL-2 therapy (720,000 IU/kg every 8 hours to a maximum of 15 doses). RESULTS: Eight patients (22%) experienced objective tumor responses (three complete and five partial), including metastases in the lungs, lymph nodes, mediastinum, and subcutaneous tissues. Six of the eight patients have ongoing objective responses at 11 to 19 months. Five patients (14%) developed grade III/IV autoimmune toxicities secondary to anti-CTLA-4 administration, including four patients with enterocolitis and one with arthritis and uveitis.

CONCLUSIONS: There is not evidence to support a synergistic effect of CTLA-4 blockade plus IL-2 administration, because the 22% objective response rate is that expected from the sum of these two agents administered alone. Durable cancer regressions were seen in patients treated with this combination.


Hi Mr. Breitfeller,


As this study is currently closed, I am now in charge of follow-up so your request was directed to me (I worked with Heather Blair while she was here so I’m familiar with your case). Hopefully this excerpt from the full protocol (UPCI #05-120) answers your question, but please let me know if you need further information. (CP-675,206 is the technical name for anti-CTLA-4)


Patients will receive intravenous administration of CP-675,206 at a dose of 15 mg/kg on Day 1 ofevery 90-day cycle. For purposes of treatment visits and scheduling, each cycle is defined as a 90-day (3 month) period. Patients may receive up to 4 doses (4 cycles) in a 12-month period
until progression of disease or intolerable toxicity. At a minimum, scheduled visits for clinical study safety assessments will occur monthly. Additional visits may be necessary at the discretion
of the Investigator.

Long term exposure to CP-675,206 is not known to be required to sustain clinical benefit.

Patients will be allowed to receive up to 4 doses in a 12-month period. By mutual agreement

between the Investigator and the Pfizer Clinician, patients exhibiting clinical benefit after 12 months may be eligible to continue therapy with CP-675,206 up to 2 additional doses for patients with a

Complete Response or 4 doses for patients with a Partial Response or Stable Disease up to a maximum of 24 months after enrollment


So I contacted Dr. Oncologist

Dear Mr Breitfeller,



"I don’t think we can draw any conclusions yet based on your experience with a single dose. However, one thing we do know is that dose does matter. Last year at ASCO, we presented data showing that higher doses of ipilimumab (10 mg/kg) were better than 3 mg/kg or 0.3 mg/kg. I once again applaud you for your efforts to understand the excellent response which you have had."


So, If a higher dose is better, don't you think we should repeat the trial with higher doseage of CTLA-4

Jimmy B

Delayed Melanoma Response Could Impact Clinical Decisions with Anti-CTLA-4 Agents.. Melanoma..Jim Breitfller

Elsevier Global Medical News. 2008 Nov 7, JS MacNeil

STOCKHOLM (EGMN) - Clinical studies of two experimental agents - tremelimumab and ipilimumab - have shown delayed and mixed responses among patients who gained control of refractory melanomas with these therapies.

Both agents come from a new class of monoclonal antibodies that seek to promote immune response by blocking cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4). In three phase II trials presented at the European Society for Medical Oncology Congress, tremelimumab and ipilimumab ultimately achieved disease control rates of 14%-29% as second-line therapies. No complete responses were reported.

Among patients classified as having progressive disease after ipilimumab treatment, however, were some people who subsequently improved. Likewise, among six patients with "mixed response" to tremelimumab were five patients who initially developed new lesions, but then had slow decreases in targeted lesions. All six were still alive at the time of the presentation.

Investigators suggested that the modified World Health Organization (WHO) criteria used to assess activity of cytotoxic agents may not capture the benefit in some patients classified with progressive disease. They cited four observed patterns of response, which were described in a poster by Dr. Kaan Harmankaya, of the department of dermatology at University of Vienna, and associates:

-Response in baseline lesions.

-Stable disease with a slow, steady decline in tumor volume.

-Response after increase in total tumor volume.

-Response in index and new lesions after the appearance of new lesions.

While delayed response is an issue for researchers, the clinical impact could be more important, according to a discussion of the tremelimumab and ipilimumab studies by Dr. Ulrich Keilholz of the Charité University in Berlin and the European Organisation for Research and Treatment of Cancer melanoma group. In comparing "classical and nonclassical efficacy assessment," he said that nonclassical assessment captures delayed efficacy, but the definitions are complicated and the issues in patient management are distinct from efficacy evaluation in studies.

"Nonclassical assessment does change the response rate, but it does not change the survival rate," Dr. Keilholz said, downplaying the importance of response measures, compared with overall survival in phase III trials.

In clinical practice, however, the physician must decide when to switch a patient from a therapy that is not working. The three trials showed that delayed efficacy does occur with these agents, but the limit appears to be week 20 after treatment, Dr. Keilholz said, adding: "I think that it is important to allow patients a certain amount of time ... but also to put a stop at a certain time point."

Tremelimumab

Dr. John M. Kirkwood, director of the Melanoma Center at the University of Pittsburgh Cancer Institute, presented the tremelimumab data from an open-label phase II trial in 251 patients (nearly all with stage IV disease), of whom 242 were evaluable. The protocol called for a 15 mg/kg dose to be delivered intravenously on the first day of up to four 12-week cycles. Sixteen (7%) patients achieved partial responses and 36 (15%) had stable disease - a clinical benefit rate of 22%.

Dr. Kirkwood said all but 1 of the partial responses lasted at least 170 days, and 11 were ongoing. Median overall survival reached 10.1 months, he said; median progression-free survival reached 2.8 months, with 15.6% of patients progression-free 6 months after treatment. Factors correlating with survival were still being analyzed. The trial was sponsored by Pfizer Inc.

Ipilimumab

The first ipilimumab trial was a multinational, open-label study of 155 patients with advanced disease that had failed previous therapies. Patients received 10 mg/kg of ipilimumab every 3 weeks for four cycles, followed by maintenance therapy at the same dose every 12 weeks from week 12 to week 60.

Dr. Vanna Chiarion Sileni of the Instituto Oncologo Veneto in Padua, Italy, reported 9 patients had partial responses and 33 had stable disease by modified WHO criteria, adding up to a disease control rate of 27% (42/155). The median duration of stable disease was 4.1 months at a median follow-up of 5.7 months, she said; 19 patients were still stable at their last assessment.

Among those classified with progressive disease were patients with the four patterns of response. Small subgroups had a "slow steady decline" in tumor volume after an initial increase in target lesions or the appearance of new lesions, she said.

In the second ipilimumab trial, Dr. Celeste Lebbé of Saint-Louis Hospital in Paris reported on a multinational dose-finding study that randomized patients with unresectable relapsed stage III or IV melanoma to 10 mg/kg, 3 mg/kg, or 0.3 mg/kg of ipilimumab given once every 3 weeks for four cycles followed by maintenance treatment once every 12 weeks.

The 10 mg/kg dose produced the best overall response rate, a composite measure of complete and partial responses, at 11%, and a disease control rate of 29% (the lowest rate, 14%, was at the lowest dose). Nearly half, 48% of 73 patients given the highest dose were alive at 1 year. Their median survival was estimated at 11 months at a median follow-up of 10.4 months.

The four patterns of response were observed in this study as well, Dr. Lebbé reported, and about 35% of patients at the highest dose had a decline in total tumor volume. Patients at this dose also had the most toxicity, she said; about a quarter had grade III adverse events, including gastrointestinal side effects in 16%. In most cases, it was manageable and reversible.

The ipilimumab studies were sponsored by Bristol-Myer Squibb and Medarex Inc, which are jointly developing the agent. Dr. Lebbé was the only investigator to disclose a conflict of interest, having served on two advisory boards for Bristol-Myer Squibb.

Dr. Kirkwood said phase III trials for both agents have been completed and are being analyzed, but applications for approval have not yet been filed. In April 2008, Pfizer halted a phase III study of tremelimumab monotherapy in advanced melanoma when interim data showed it would not be superior to standard therapy.

http://www.oncologystat.com/news-and-viewpoints/news/Delayed_Melanoma_Response_Could_Impact_Clinical_Decisions_with_Anti-CTLA-4_Agents_US.html

Delayed Melanoma Response Could Impact Clinical Decisions with Anti-CTLA-4 Agents


I believe the delayed response was what happen to me.

Jimmy B