A very Happy Father's Day from a stage IV Melanoma Survivor..Jim Breitfeller

I want to thank all the people that has made this day a very special Day.


As a stage IV Melanoma Survivor, I never dreamed that I would be here today to witness my children spread their wings and learn to fly. My daughter was just entering college when I was first diagnosed and my son, Chris was a sophmore in High School. Today, I am preparing to help my son relocate to Connecticut. He just landed an engineering job at an areospace company. My daughter, Jessica is globe-trotting around the world working on her dual Masters in "International Affairs" and "Natural Resources & Sustainable Development". This day, marks Dee and I as offically "Empty Nesters".

This all was made possible by entering a journey that entailed four clinical trials along with the best and internationally renowned medical team that makes climbing Mt. Everst apiece a cake. And you , My carepage friends that kept me on the "Yellow Brick Road". I have won the "lottery of life."

Many Thanks

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

Take Care,

 Jimmy B
 

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

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

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

Dr. Steven Rosenberg is using engineered T-cells that secrete IL-12 to stimulate Th cells to secrete Th1 cytokines. This sets in motion the positive feed back loop needed to initiate an immune response. His therapy is show great promise. “It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.” ~Charles Darwin~ Take Care, Jimmy B

The missing third signal "The Danger Signal"Melanoma..Jim Breitfeller

Th17 Cells Secrete IL-17 in the Tumor Microenvironment causing inflammatory symptoms "The Danger Signal"improves Survival in a Murine Model of Pancreatic Cancer and in Melanoma also.

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

"Th17 cells and IL-17 participate in antitumor immunity by facilitating T cell recruitment to the tumor site and CD8+ T cell priming and effector differentiation suggests a new avenue for developing Th17 cell-based therapy."

~S. A. Rosenberg~


"Using in vitro and in vivo approaches, we determined that under neutral conditions, simultaneous activation of Tregs and naive CD4+ conventional T cells in the presence of APCs resulted in conversion of Tregs into IL-17–producing cells, and endogenous IL-1β was mandatory in this process" according to Vassiliki A. Boussiotis et al



Thus, the addition of IL-6 and IL-1β to the tumor microenvironment skews the balance toward Th17 cells in a murine model of pancreatic cancer and Melanoma.

So we need to suppress the Tregs and generate Th17 T-cells to initiate the right immune response.




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

The Missing Link in T-cell activation using a Vaccine, "The Danger Signal"Melanoma..Jim Breitfeller

As I research why some patients respond to therapies i.e. vaccination and other immunotherapy and others don’t, I ask WHY? In my quest to get the answer or answers, I came across a paper called “Marked Differences in Human Melanoma Antigen-Specific T Cell Responsiveness after Vaccination Using a Functional Microarray”.

Daniel S. Chen1,2#, Yoav Soen3#, Tor B. Stuge4, Peter P. Lee4, Jeffrey S. Weber5, Patrick O. Brown2,3, Mark M. Davis2,6*

1 Department of Internal Medicine/Division of Oncology, Stanford University, Stanford, California, United States of America, 2 Howard Hughes Medical Institute, Stanford University, Stanford, California, United States of America, 3 Department of Biochemistry, Stanford University, Stanford, California, United States of America, 4 Department of Medicine, Stanford University, Stanford, California, United States of America, 5 Norris Cancer Center, University of Southern California, Los Angeles, California, United States of America, 6 Department of Microbiology and Immunology, Stanford University, Stanford, California, United States of America



This is what I was looking for. It may hold the answer or could possibly point me in the right direction.

In the paper I came across a diagram that peaked my interest. It was a comparison between responders and non-responders.

They were looking at the cytokines secreted after the vaccine was given. When I saw what the cytokines were, I knew I was on the right track. These cytokines help in the differentiation of the CD4+ T-cells. What a find!!




Naïve CD4 T cells in the presence of TGF-b and IL-2 and others differentiate into Tregs.

TGF-b accelerates the CTLA-4 expression by stimulated CD4+ CD25- T-cells.

TGF-b requires CTLA-4 early after T-cell activation to induce FoxP expression generating CD4+ CD25+ Treg Regulatory cells.

The Th-17 cells produce IL-17. .IL-17 induces the production of many other cytokines (such as IL-6, G-CSF, GM-CSF, IL-1β, TGF-β, TNF-α).



So what was the non-responder missing, IL-6. With the missing IL-6, they weren’t able to produce Th-17 that secreted IL-17.

While TGF-β is a critical differentiation factor for Treg cells, IL6 completely inhibits the generation of Treg cells induced by TGF-β. Instead, IL6 and TGF-β together induce the differentiation of pathogenic Th17 cells. With IL-6 missing in the microenvironment, Treg Cells flourish.

If the CD4 + T cells differentiate into TH2 cells that produce IL-4, the other cells inhibited to produce IL-6. IL-4 was found to inhibit TNF-α and IL-1β by activated monocytes almost 100 %. The Secretion of IL-6 was decreased by approximatly 80 % in the presences of IL-4 Cytokine. TE Velde et al 1990

They were missing “The Danger Signal”.

Friendly inflammation “The Danger Signal”

Most of the time you have no notion of the microbial life-and-death struggle being waged within your body. At other times, though, you are acutely aware of the exact location of the battleground, thanks to the unmistakable signs of inflammation — heat, pain, redness, and swelling. Inflammation, the buildup of fluid and cells at the point of infection/cancer, is put into motion by cytokines — proteins that are released into the blood by the innate immune system when it encounters germs. Cytokines function like police dispatchers. They signal there's a problem, which activates the immune system's highway patrol force: the circulating lymphocytes of the adaptive immune system. These lymphocytes cruise the highways of the blood vessels and lymphatic system. In response to the chemical signal from the cytokines, increased blood flow rushes these circulating cells to the trouble spot.

“The CD8+ T-cell-mediated Immune Response to Eradicate the Tumors”

“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 . Therefore, this event depends entirely on appropriate antigen presentation, which is most efficiently provided by mature dendritic cells. Peripherally tolerant or “ignorant” self-reactive T-cell clones, once properly activated, may serve as tumor-specific effector T cells .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. 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, IL-17 and IFN-γ provide a third signal that acts directly on T cells, referred to as the “danger signal”.

This signal was found to optimally activate TH1 differentiation and lead to clonal expansion of T cells.

The responder was able to produce inflammatory cytokines, including IL-1, IL-6, IL-12, IL-17 and IFN-γ provide a third signal that acts directly on T cells, referred to as the “danger signal”.

This signal was found to optimally activate TH1 differentiation and lead to clonal expansion of T cells and invoke a robust immune response to the Melanoma Cancer.

“Our data altogether suggest the following model: Th17 cells go to the tumor site and, by secreting IL-17, activates residential cells to produce CCL2 and CCL20, which provokes the mobilization of DCs and other leukocytes to the tumor site. DCs uptake tumor antigens in the lung or tumor site and migrate to the lymph nodes where they activate CD8+ T cells against the tumor. The new wave of effector CD8+ T cells migrates back to the lung or tumor site and kills established tumors.

Therefore, our data demonstrating that Th17 cells and IL17 participate in antitumor immunity by facilitating T cell recruitment to the tumor site and CD8+ T cell priming and effector differentiation suggests a new avenue for developing Th17 cell-based therapy for tumors or chronic viral infections and as an adjuvant for vaccinations.”

(Dudley and Rosenberg, 2007; Rosenberg and Dudley, 2004)

Conclusion: We not only want to supress the Tregs, we also need to produce the "Danger Signal" to optimally activate TH1 differentiation and lead to clonal expansion of T cells to generate a robust tumor-specific immune response.






The Missing Link in T-cell activation using a Vaccine, "The Danger Signal"


“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

Applying Dosing Schedules to the Protocols of Combo Therapy, Optimize the clinical outcome 4-14-2010 Note to Rosenberg Melanoma Jim Breitfeller

Applying dosing schedules to the clinical protocols of combinatorial therapy, we can optimize the clinical outcome 4-14-2010 Note to Dr. Rosenberg
In 1986, a clinical protocol for the treatment of advanced malignant melanoma with
the newly discovered class of immune cells called TIL was initiated at the National Institutes of Health (NIH). These lymphocytes are T cells that are isolated directly from the tumor and that are then grown to large numbers in tissue culture in the presence of the T cell growth factor interleukin-2 (IL2). After expansion in culture several thousand times, approximately 2 X 10" TIL are given to the patient intravenously in addition to high doses of IL-2 in several days of treatment. Even in those patients who did not respond to all other therapy (including treatment with IL-2 alone), 35 to 40% of patients responded to this protocol.

The large-scale tissue culture and the large numbers of cells and IL-2 that are given to a patient make this procedure expensive and clinically difficult. Furthermore, 60 to 65% of patients fail to respond to this treatment, and even those who do respond will often fail after 6 to 12 months. It is likely that only a subset of the heterologous population of cells administered to a patient are effective in killing cancer cells in vivo.

That was then (1986) and this is now 2009. Dr. Rosenberg and colleagues have optimized the protocol to generate a response rate of 72% using lymphodepletion prior to Adaptive Cell Therapy.

It cannot be certain that the TIL subsets preferentially recovered from the tumor biopsy corresponded to those that mediated complete elimination of tumor in this patient.

Recently, a patient that went down to NIH and did the ACT therapy had a response only where the cells came from (lungs). The other tumors continued to progress.

Are the TILs tumor specific based on where the cells were obtained during biopsy? Does this mean the other tumors mutated or are they missing some receptor or MHC I or II at the tumor surface?


Adoptive Cell Transfer.. 57 days after transfer. CD8+ T-cell (CTLs) at the Maximum Propagation


A tumor lesion excised from patient 9 before nonmyeloablating chemotherapy ("pretreatment") exhibited scant CD8+ cells (left), strong stromal cell staining but weak staining of tumor cells with antibody to MHC class I (center), and sporadic cell staining with an antibody to MHC class II (probably tumor macrophages) but minimal staining of tumor cells (right). In contrast, a sample resected 57 days after cell transfer ("post treatment") exhibited a dense, diffuse CD8+ infiltrate and ubiquitous expression of both MHC class I and class II molecules in tumor cells.

Source: Cancer Regression and Autoimmunity in Patients After Clonal Repopulation with Antitumor Lymphocytes
Originally published in Science Express on 19 September 2002
Science 25 October 2002:
Vol. 298. no. 5594, pp. 850 - 854
DOI: 10.1126/science.1076514


Patients undergoing Anti-CTLA-4 Blockadge. Week7 = Day 49 maximum ALC.. CD8+ T-cell (CTLs)

Source: Dr. Jedd Wolchok





What I am trying to show is the growth curves for the various T-cells subsets with data from in vivo to back up the above graphic. With that in mind, we now have a better understanding on the growth patterns of these cells. By applying dosing schedules to the clinical protocols of combinatorial therapy, we can optimize the clinical outcome

Take Care,

Jimmy B

Letter to Dr. Rosenberg on Combinatorial Therapy using Anti-CTLA-4 Blockade and High Dose Interleukin -2 3-19-2010 Melanoma..Jim Breitfeller

Dr. Rosenberg, during my search for answers about my therapy, I took notice of a combinatorial trial that you headed in 2003.

Study Start Date: February 2003

Detailed Description:

OBJECTIVES:

• Determine the maximum tolerated dose (MTD) of anti-cytotoxic T-lymphocyte-associated antigen-4 monoclonal antibody (MDX-CTLA4) in combination with high-dose interleukin-2 (IL-2) in patients with metastatic melanoma. (Phase I is closed to accrual as of 4/13/2004).

• Determine the activity of MDX-CTLA4 administered at the MTD with high-dose IL-2 in these patients.

• Determine whether the administration of IL-2 alters the pharmacokinetics of MDX-CTLA4 in these patients.

• Determine the safety and adverse event profile of this regimen in these patients.
OUTLINE: This is an open-label, dose-escalation study of anti-cytotoxic T-lymphocyte-associated antigen-4 monoclonal antibody (MDX-CTLA4).

• Phase I: Patients receive MDX-CTLA4 IV on days 0, 21, and 42. Patients also receive high-dose interleukin-2 (IL-2) IV over 15 minutes every 8 hours for up to 15 doses beginning on days 22 and 43. Treatment repeats every 63 days for up to 3 courses in the absence of disease progression or unacceptable toxicity. Patients with an ongoing partial response and no greater than grade 1 toxicity may receive additional courses of therapy. Patients who require discontinuation of MDX-CTLA4 due to toxicity may continue receiving IL-2 at the discretion of the investigator.

Cohorts of 3-6 patients receive escalating doses of MDX-CTLA4 until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. (Phase I is closed to accrual as of 4/13/2004).

• Phase II: Patients receive treatment as in phase I at the MTD of MDX-CTLA4. Patients who achieve a partial or complete response and later develop recurrent or progressive disease may be retreated at the same dose.

Patients are followed at 3 weeks, every 3 months for 1 year, every 6 months for 2 years, and then annually thereafter.

PROJECTED ACCRUAL: A total of 3-51 patients (3-18 for phase I and 19-33 for phase II) will be accrued for this study within 1 year. (Phase I is closed to accrual as of 4/13/2004).

Based on knowledge gained over the last decade, I believe it warrants us/you to revisit this combinatorial approach.

Base on Dr. Wolchok’s research, the dose of the anti-CTLA-4 was to low to shift from tolerance to activation. Also, the addition of the HD IL-2 was added at the time to proliferate the CD4+ T-cells which may have caused a five fold expansion of the Tregs. There is now new data that suggests that IL-2 addition should be added after the contraction of the CD4+ T-cells. Et al Wherry.

By adding the The HD IL-2 after the expansion of the T-cells, IL-2 therapy was highly beneficial during the death phase, resulting in increased proliferation and survival of tumor-specific T cells. IL-2 treatment also increased proliferation of resting memory T cells.

If you add the combination of IL-2 and TGF- beta (tumor secreted) at the beginning of the treatment, it induces naive or total CD4+CD25– cells to develop strong suppressive effects both in vitro and in vivo according to Horwitz et al 2001. The T-Cell differentiation is pushed towards developing Treg suppressive immune cells.
So increasing the dose of Anti-CTLA-4 Blockade and delaying the addition of the HD IL-2 can have a dramatic effect on the overall response of the immune system. Here is a graphic representation of the protocol.







I know you will get a synergistic response with this protocol because it happen to Dr. Vivian Bucay and myself.







Please, if you get a chance, consider this new protocol and revisit the combinatorial
therapy of Anti-CTLA-4 Blockade and HD IL-2.

Thanks for you time

Best regards,

Jim Breitfeller

Melanoma and The Magic Bullet (Monoclonal Antibodies)


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


Eureka!!!!!! A possible cure for Melanoma, the Deadly Skin Cancer




Take Care,

Jimmy B

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

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

The paper that I am about to present to you is a culmination of research that was done base on my own experience as a stage IV Melanoma Patient. I wanted to know why my immune system responded and prove to myself and my doctors that it was not a statistical fluke. I dedicate this paper to all my fellow Melanoma Patients that lost their battle with the Beast, especially Bob Luker who fought so bravely but was unable to obtain Anti-CTLA-4 blockade due to the shortage proclaimed by Bristol Myer Squibb which halted compassionate drug use on 9-12-2008.

Most Melanoma tumors are accepted by the host’s immune system and progress even when they contain potentially antigenic proteins. This may be due to the tumor secreting immunosuppressive Cytokines like, TGF-Beta, IL-10, IL-4 and IL-6. TGF-β inhibits the proliferation and functional differentiation of T lymphocytes. TGF- Beta accelerates the expression of CTLA-4 by stimulated CD4+CD25– T cells. TGF- Beta requires CTLA-4 early after T Cell Activation to induce FoxP3 and generates adaptive CD4+CD25+ (Treg) Regulatory Cells. The tumor cells secrete TGF-Beta.

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




Take Care,

Jimmy B

Cancer Immunotherapy: What Do We Know and How Did We Learn It?Melanoma..Jim Breitfeller

Steven A. Rosenberg

Surgery Branch, National Cancer Institute, Bethesda, MD, USA

"In the past two decades immunotherapy approaches have been shown to be effective for the treatment of selected patients with metastatic cancer. The administration of interleukin-2 or a monoclonal antibody against CTLA-4 can mediate regression of metastatic melanoma in about 15% of patients. The administration of in vitro expanded autologous anti-tumor T cells, plus IL-2, following a lymphodepleting chemotherapy results in objective regressions in 50% of patients with metastatic melanoma. In a recent trial adding total body irradiation to the preparative regimen, an objective response rate of 72% was seen including 32% of patients with a complete response, all but one ongoing beyond two years1,2. T cells capable of mediating these regressions have been used to identify dozens of human cancer antigens3. Recently gene therapy approaches that utilize the transduction of genes encoding anti-tumor T cell receptors has resulted in objective cancer regressions4,5. This latter approach is now being applied to the immunotherapy of patients with common epithelial cancers."


source:http://web.ncifcrf.gov/events/cancervaccine/ProgramBook.pdf


References
1.
Dudley, M.E., Wunderlich, J.R., Robbins, P.F., Yang, J.C., Hwu, P., Schwartzentruber, D.J., Topalian, S.L., Sherry, R., Restifo, N.P., Hubicki, A.M., Robinson, M.R., Raffeld, M., Duray, P., Seipp, C.A., Rogers-Freezer, L., Morton, K.E., Mavroukakis, S.A., White, D.E., and Rosenberg, S.A.: Cancer regression and autoimmunity in patients after clonal repopulation with anti-tumor lymphocytes. Science 298:850-854, 2002.
4
2.
Dudley, M.E., Yang, J.C., Sherry, R., Hughes, M.S., Royal, R., Kammula, U., Robbins, P.F., Huang, J., Citrin, D.E., Leitman, S.F., Wunderlich, J., Restifo, N.P., Thomasian, A., Downey, S.G., Smith, F.O., Klapper, J., Morton, K., Laurencot, C., White, D.E., and Rosenberg, S.A.: Adoptive cell therapy for patients with metastatic melanoma: Evaluation of intensive myeloablative chemoradiation preparative regimens. J. Clin. Oncol., 26:5233-5239, 2008.
3.
Rosenberg, S.A.: Progress in human tumour immunology and immunotherapy. Nature 411:380-384, 2001.
4.
Morgan, R.A., Dudley, M.E., Wunderlich, J.R., Hughes, M.S., Yang, J.C., Sherry, R.M., Royal, R.E., Topalian, S.L., Kammula, U.S., Restifo, N.P., Zheng, Z., Nahvi, A., de Vries, C.R., Rogers-Freezer, L.J., Mavroukakis, S.A., and Rosenberg, S.A.: Cancer regression in patients after transfer of genetically engineered lymphocytes. Science 314:126-129, 2006.
5.
Johnson, L.A., Morgan, R.A., Dudley, M.E., Cassard, L., Yang, J.C., Hughes, M.S., Kammula, U.S., Royal, R.E., Sherry, R.M., Wunderlich, J.R., Lee, C-C. R., Restifo, N.P., Schwarz, S.L., Cogdill, A.P., Bishop, R.J., Kim, H., Brewer, C.C., Rudy, S.F., VanWaes, C., Davis, J.L., Mathur, A., Ripley, R.T., Nathan, D.A., Laurencot, C.M., and Rosenberg, S.A.: Gene therapy with human and mouse T-cell receptors mediates cancer regression and targets normal tissues expressing cognate antigen. Blood 114:535-546, 2009


When you put together all that we know, Treg surpression,Anti-CTLA-4 Blockage and IL-2 growth factor, Oncologists have the tools to stabilize Melanoma. In some cases, they may have even cured Melanoma. Time will only tell.



Melanoma And the Magic Bullet, (Monoclonal Antibodies)



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~

Effective Immunotherapy for Patients with Metastatic Melanoma..Jim Breitfeller

Steven A. Rosenberg, MD, PhD
Chief of Surgery, National Cancer Institute
National Institutes of Health, Bethesda, MD

Immunotherapy has emerged as the most effective treatment for patients with metastatic melanoma. Much of the information concerning the immune response to melanoma has come from the study of tumor-infiltrating lymphocytes (TIL), immune cells that infiltrate into the stroma of the growing tumor and can be grown in vitro in the cytokine IL-2.1 TIL have been used to identify dozens of antigens that are presented on melanomas.2 Some antigens such as MART-1 and gp100 are shared by both melanomas and normal melanocytes, whereas others, such as NY-ESO-1, can be expressed on melanomas, but on no other adult tissue except the testes.

Most studies of immunotherapy for melanoma patients have been directed at those with metastatic disease. Although multiple trials of cancer vaccines have been performed in patients with resected lymph nodes at high risk of recurrence, none of these clinical trials have convincingly demonstrated prolonged survival.3 Some controversy exists surrounding the use of interferon alpha for the treatment of stage 3 melanoma; prolonged follow-up of patients in prospective randomized trials has yielded ambiguous results, and many oncologists are concluding that the toxicities of highdose interferon are not warranted given the lack of conclusive evidence of effectiveness in this setting.

Substantial progress has been made, however, in the treatment of patients with metastatic melanoma. It is now possible to cause complete regressions of widely metastatic melanoma at multiple sites in the body utilizing immunotherapy approaches. Immunotherapy Approaches To Metastatic Melanoma Approaches to the treatment of patients with metastatic melanoma fall into three major categories, which are summarized in Table 1 at Effective Immunotherapy for Patients with Metastatic Melanoma


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

A Call for Patients for Dr. Rosenberg's Clinical Trials

"We continue to see a high rate of clinical responses in our cell transfer immunotherapy treatments for patients with metastatic melanoma", Dr. Rosenberg said.

"We are actively seeking patients for these trials and any note of that on a patient-directed web site would be appreciated."

If you would like to apply for his trials, here is the website and information.



Dr. Rosenberg's information




Dr. Rosenberg's Clinical Trials






Take Care,

Jimmy B

IL-2 administration increases CD4 + CD25(hi) Foxp3+ regulatory T cells in cancer patients.Melanoma..Jim Breitfeller

Ahmadzadeh M, Rosenberg SA.

Surgery Branch, NCI, NIH, Bethesda, MD 20892, USA.

Interleukin-2 (IL-2) is historically known as a T-cell growth factor. Accumulating evidence from knockout mice suggests that IL-2 is crucial for the homeostasis and function of CD4+ CD25+ regulatory T cells in vivo. However, the impact of administered IL-2 in an immune intact host has not been studied in rodents or humans. Here, we studied the impact of IL-2 administration on the frequency and function of human CD4+ CD25(hi) T cells in immune intact patients with melanoma or renal cancer. We found that the frequency of CD4+ CD25(hi) T cells was significantly increased after IL-2 treatment, and these cells expressed phenotypic markers associated with regulatory T cells. In addition, both transcript and protein levels of Foxp3, a transcription factor exclusively expressed on regulatory T cells, were consistently increased in CD4 T cells following IL-2 treatment. Functional analysis of the increased number of CD4+ CD25(hi) T cells revealed that this population exhibited potent suppressive activity in vitro. Collectively, our results demonstrate that administration of high-dose IL-2 increased the frequency of circulating CD4+ CD25(hi) Foxp3+ regulatory T cells. Our findings suggest that selective inhibition of IL-2-mediated enhancement of regulatory T cells may improve the therapeutic effectiveness of IL-2 administration.


Just thought you might like to Know!!!

Take Care,

Jimmy B

Inducing a Immune Response.. Melanoma ..Jim Breitfller

The best way to fight cancer (Melanoma) in my opinion is to have your own immune system do the work. First one must activate the T-cells.
Activation of T cells requires both engagement of the (TCR) T Cell Receptor with a cognate peptide–MHC complex and an additional costimulatory signal. The antigen must be in the right configuration and be specific to the cancer. The antigen becomes part of the MHC complex. The T cell receptor is restricted to recognizing antigenic peptides only when bound to appropriate molecules of the major histocompatibility complex (MHC), also known in humans as Human leukocyte antigen (HLA).
Secondly one must have a co-simulative signal.

The best known co-stimulatory ligands (proteins) are members of the B7-family, B7-1 (CD80) or B7-2 (CD86), that are expressed on professional antigen-presenting cells (APCs) such as dendritic cells (DCs); these act through their receptor CD28 on T cells CTLA-4 (CD152) is a second receptor for CD80 and CD86, which is not expressed on most resting T cells but is induced upon T-cell activation. The interaction of CD80/CD86 with CTLA-4 has higher affinity than that with CD28, and down-regulates T-cell activation . Thus, CTLA-4 effectively competes with CD28 for CD80/ CD86 at later stages of the immune response to suppress the activation and bring about activation-induced nonresponsiveness (AINR) and/or activation-induced cell death (AICD). Down-regulation of T-cell function by CTLA-4 engagement appears to play a key role in development of T-cell tolerance or anergy towards self- or tumor antigens while antigenic stimulation in the absence of co-stimulatory signals is also tolerogenic.

So by introducing anti-CTLA-4, one can block the down-regulation of the T-cell and keep it activated for a longer period of time. By anti-CTLA-4 blockage, one can suppress the Treg and change the balance of the immune system to respond to the APC. Here is a list of Costimulatory receptors on T –Cells:

• CTLA-4
• PD-1
• 4-1BB
• HVEM
• CD 30
• OX40
• CD28
• CD27

By Treg depletion, you can also break the balance of anergy. Dr. Rosenberg uses Treg depletion prior to Adoptive Cell Transfer therapy.

Bottom line is you need to invoke this type activation to orchestrate an immune response.

Take care

Jimmy B

A letter to my Congressman. Melanoma .. Jim Breitfeller

I hope to make contact with my Congressman tonight.

Here is a copy of that letter:

Congressman Dan Maffei,

I have a story to tell.

Last July (2005) I was riding my bicycle to work at the Eastman Kodak Research Labs about 3 miles from home; I was wearing a knapsack to carry my things to and from the labs. I started noticing an ache on my back. So I decide to go to the dermatologist. To make the log story short, it was cancer. Melanoma.

Over 64000 a year are diagnosed with Melanoma and 8500 will die this year alone. There is no cure for this type of cancer and if you progress to a stage IV were it has metastized, you usually have 6 to 9 months to live.

Anyway, I had to go out of state to get the specialized treatment. In doing so, I did four clinical trials to try to save my life. The last two were immunology therapy. One was anti-CTLA-4 blockage (Monoclonal antibodies) and the other was high dose Interluekin-2 (IL-2). These combinations of therapy just so happen to jump start my immune system. At the time of the therapies I had 40+ tumors in my Lungs.
Today 26 months, I am (NED) no evidence of disease.

So being a researcher by profession at Eastman Kodak for 25 years (I hold a couple of patents that I helped coauthored), I began to research and piece together why my treatment has worked. I have contacted Dr. Steven a Rosenberg and other colleagues to review my Theory.

Here are just some of the responses from the Clinical Oncologists:

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

“May I forward this to one of my colleagues? He may have some insights.”

“Thanks for your note. You really refreshed my mind! I am glad things have worked out relatively well for you!. Did you get rid of your disease? I am glad you are writing your story and hopefully inspiring a number of patients in dire need of hope. Let me know how can I help.”

“Thank you so much for sharing your experience and thoughts.
Some patients have indeed experienced tantalizing responses after treatment with CTLA4 antibodies. Let me assure you that many of us in the field keep working hard on figuring out what explains those successes so that, armed with that knowledge, we can extend the benefit to many cancer patients. Experts agree that the way forward requires combinations of immunotherapies. Despite the many obstacles (scientific, regulatory, operational, intellectual property, economic, etc), Pfizer Oncology is moving decisively in that direction.”



“Congratulations,
I think you may find our ASCO abstracts interesting this year. Especially the one that talks about the time dependent variability of immunoreactivity in patients with melanoma.”

(ASCO) is the American Society of Clinical Oncology. The meeting this will be held on May 31-June 2, 2009 in Florida.

As you can see, I am trying to get the word out and hopefully gain some traction. I have tried to contact the two drug companies because this treatment/ theory involves their two drugs and they must be used in concert together to obtain a synergic immune response.

Dr. Rosenberg and colleagues did a trial at the NCI but the dosage and the timing of each of the drugs were not done at optimal conditions at the time. Based on my theory and other researchers now know that there is a “time dependent variability of immunoreactivity in patients with melanoma” and that a higher dose is needed to obtain a immune response.

“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.”

As you can see, I am passionate in finding a cure/stabilization. I have come to you as my representative, to ask for your assistance to help further this cause because I believe this will benefit the Nation as a whole and even the world as it pertains to today. We need to get this Drug FDA approved as soon as possible.

We can stand up to cancer and Move Mountains if we all work together!!!!!!!!!!


Thank you for your time and I hope to hear from you soon.

Please don’t let this fall on deaf ears. I will volunteer to help move this forward. We owe it to the 65000+ patients in Our Country and the world.


Sincerely,



James M. Breitfeller ( Patient/Survivor/Researcher of Melanoma Stage IV)

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 Medarex 3-24-2009 Melanoma Jim Breitfeller

Ms wolfe,
This not about who has what product? This about a theory and therapy that will make your product the greatest invention since sliced bread. Your product has the potential of help cure Melanoma. The dose has to be 15mg/Kg to invoke an innate immune response. Once that has happen, the Interluekin -2 (growth factor) promotes propagation and is need to activate the CD8+ Tcell. IL-2 Regulates Perforin and Granzyme Gene Expression in CD8+ T Cells Independently of Its Effects on Survival and Proliferation. With all this said and done, IL-2 needs the get Immune response started. That is done by your Monoclonal Antibody. “The Magic Bullet”.

Well now I have a request for you. Please pass this on to your Clinical Team. I have been data mining on the internet and have been able to piece together why my combination therapy worked. etc...........

The rest is the same as Dr. Rosenburg Letter.

I am still trying to make contact with Novartis the, Manufacturer of Interluekin-2. I don't have a contact name or email yet. I hope to get one soon. If any one has a contact please get intouch with me.

Thanks

Jimmy B

Cutting Edge Technology “Infection-mimicking materials to program dendritic cells in situ”Melanoma .. Jim Breitfeller

Cutting Edge Technology “Infection-mimicking materials to program dendritic cells in situ”

Thanks to Donald Bohlken for bring this to my attention.

“I thought you might be interested in that attached article from the January 25, 2009 issue of the journal "Nature Materials" concerning a Harvard study of a new vaccine methodology which resulted in a 90% survival of mice infected with a melanoma strain which would normally kill them in 25 days. The article speaks of this result as a "cure".

The article synopsis notes: "Cancer vaccines typically depend on cumbersome and expensive manipulation of cells in the laboratory, and subsequent cell transplantation leads to poor lymph-node homing and limited efficacy. We propose that materials mimicking key aspects of bacterial infection may instead be used to directly control immune-cell trafficking and activation in the body. It is demonstrated that polymers can be designed to first release a cytokine to recruit and house host dendritic cells, and subsequently present cancer antigens and danger signals to activate the resident dendritic cells and markedly enhance their homing to lymph nodes. Specific and protective anti-tumour immunity was generated with these materials, as 90% survival was achieved in animals that otherwise die from cancer within 25 days. These materials show promise as cancer vaccines, and more broadly suggest that polymers may be designed to program and control the trafficking of a variety of cell types in the body."
This is Nano and Transdermal Technology at its best.

Implants Mimic Infection To Rally Immune System Against TumorsMain Category:

Melanoma / Skin CancerAlso Included In: Immune System / Vaccines; Medical Devices / Diagnostics; Biology / Biochemistry

Article Date: 25 Jan 2009 - 0:00 PST

“Bioengineers at Harvard University have shown that small plastic disks impregnated with tumor-specific antigens and implanted under the skin can reprogram the mammalian immune system to attack tumors.

The research -- which ridded 90 percent of mice of an aggressive form of melanoma that would usually kill the rodents within 25 days -- represents the most effective demonstration to date of a cancer vaccine.

Harvard's David J. Mooney and colleagues describe the research in the current issue of the journal Nature Materials.

"Our immune systems work by recognizing and attacking foreign invaders, allowing most cancer cells -- which originate inside the body -- to escape detection," says Mooney, Gordon McKay Professor of Bioengineering in Harvard's School of Engineering and Applied Sciences. "This technique, which redirects the immune system from inside the body, appears to be easier and more effective than other approaches to cancer vaccination."

Most previous work on cancer vaccines has focused on removing immune cells from the body and reprogramming them to attack malignant tissues. The altered cells are then reinjected back into the body. While Mooney says ample theoretical work suggests this approach should work, in experiments more than 90 percent of the reinjected cells have died before having any effect.
The implants developed by Mooney and colleagues are slender disks measuring 8.5 millimeters across. Made of an FDA-approved biodegradable polymer, they can be inserted subcutaneously, much like the implantable contraceptives that can be placed in a woman's arm.
The disks are 90 percent air, making them highly permeable to immune cells. They release cytokines, powerful attractants of immune-system messengers called dendritic cells.
These cells enter an implant's pores, where they are exposed to antigens specific to the type of tumor being targeted. The dendritic cells then report to nearby lymph nodes, where they activate the immune system's T cells to hunt down and kill tumor cells throughout the body.”

Source: Http://www.medicalnewstoday.com/articles/136473.php

Implants Mimic Infection To Rally Immune System Against Tumors



Donald Bohlken actually contacted one of the collaborators, Dr. Glenn Dranoff of the Dana Farber Cancer Institute and Harvard Medical School. He indicated: "We are initiating efforts to bring this to clinical testing, but it will take some time to adapt the procedures to patients. A one year time frame is a reasonable guess."

If this crosses over from the mouse model to the human model, we may have a winner on our hands. A 90 % response and if they are complete responses, this technology would surpass any therapy out there to date. The main take away is that they are prompting our immune system to recognize the tumors by activation of the T-cell. Rosenberg and Hwu and other colleagues are doing just that with (ACT) Adoptive Cell Transfer. Kirkwood, Camacho, Webber, Hodi, Maker, O’Day and Wolchok did that with anti-CTLA-4 blockage.

I can see the Light at the end of the tunnel!!!!!!!!!!!!!!!!!!!!!!!!!!!

Thank you Don for advocating for us and your Brother Ron who is a fighting Warrior of Melanoma.

I will post the research paper on Melanoma Missionary for everybody.

Jimmy B

Comparison Between the two Therapies Melanoma..Jim Breitfeller

This is all base in the reseach paper from 1988.4. Itoh, K; Platsoucas, CD; Balch, CMAutologous 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 1419-1441http://jem.rupress.org/cgi/reprint/168/4/1419.pdf
Activation by Interleukin 2 and Autologous Tumor Cells, and Involvement of the T Cell Receptor


And YES, Dr. Kirkwood's therapy is only one Data point.

But I am Happy to be that data point!!!!!
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

The Orchestration of an Inmmune Response Unrehearsed Melanoma..Jim Breitfeller

The Orchestration of an Inmmune Response Unrehearsed

In 2006, after two fail attempts (Interferon and Dacarbazine with Patrin) to stop the progression of my melanoma, I was able try CTLA-4 Blockage. It was one of my first choices, but due to protocol, I had to try the FDA approved therapy first. I had researched this monoclonal antibody. On 10-24-2005 when I was first diagnosed with melanoma, I contacted Dr. Luis H. Camacho who was currently at MD Anderson.

Subject: Paper on Antitumor Activity

“Luis Camacho, My name is Jim Breitfeller and I have recently been diagnosed with melanoma will need some sort of Ontological therapy after my surgery. I ran across an abstract of yours (Antitumor activity in Melanoma and anti-self responses in Phase 1 trials with the anti-Cyctotoxic T Lymphocyte-Associated Antigen 4 Monoclonal Antibody CP-675,206) in the Journal of Clinical Oncology. Is it possible to get a copy of your paper? It can be emailed to the address below.”

Camacho response:

Dear James,

Thank you for your note. The CTLA4 antibodies in melanoma are currently under development and completing the approval process with the FDA (Phase II and Phase III). The overall response rates in my mind will be near 20-30% with a good number of patients attaining long term remissions. However, none of the programs are currently oriented to patients rendered NED (Stage III or IV). They are in fact for patients with advanced disease. From your brief introduction, I think your best options are to obtain an HLA typification and go for an adjuvant trial.

Please feel free to page me if you need further information. Pager is 713.404-5319
Best,

Luis

CP-675,206, a novel monoclonal antibody, enlists the immune system to fight advanced melanoma

Some Positive Test results of the CTLA-4

"Early testing of an experimental human monoclonal antibody showed a striking benefit in patients with advanced melanoma, say researchers at The University of Texas M. D. Anderson Cancer Center, who presented their findings at the annual meeting of the American Society of Clinical Oncology. Of 39 patients given a single injection of CP-675,206 (known as CP-675), tumors disappeared in three patients, shrunk in a fourth patient, and cancer stopped growing in five other patients. These responses have remained since their initial treatment, which ranged from 13 to 28 months ago.

Most of the patients in the trial had advanced melanoma, which has a median survival of less than a year, says the study's principal investigator, Luis Camacho, M.D., MPH, assistant professor in the Department of Melanoma Medical Oncology.

"We were very pleasantly surprised to find such objective antitumor responses in a Phase I clinical trial, which is designed to find the ideal dose and to look for side effects," says Camacho. "These results are very early, but they are encouraging to us because there are no good agents available to treat melanoma once it has spread."

Source: Laura Sussman from (ASCO) American Society of Clinical Oncology

At the time of the request, I was not at the correct stage but I knew that this might be the path of the future. I did contact him and we discussed my options at that time. I was just learning the ropes.

On 9/3/06 I contacted Dr. Rosenberg just in case I needed a back up plan if the CTLA-4 blockage did not work. At that time I did not know I was the wrong HLA-02 type for Rosenberg’s trials.

“I am Contacting Dr. Steven A. Rosenberg at the National Cancer Institute in Bethesda, Maryland.

He is the lead the researcher on the Gene Therapy Trials.
Log onto the CBS website for the story!!!!!!
http://www.cbsnews.com/stories/2006/08/31/health/main1955526.shtml
The research team recently applied to the Food and Drug Administration (FDA) to try the new cells in about 100 patients. The FDA is expected to respond to the request by mid-September.

Dr. Rosenberg, I just got the news of your Gene Therapy Experiments. The initial results look somewhat promising. I applauded you and your team for making great strides in the cure for melanoma cancer.

I am a cancer patient (48 yrs. old) under the care of Dr. John Kirkwood at the Hillman Cancer Center at the University of Pittsburgh. I have gone through a wide incision, lymph nodes removal, Interferon therapy, and Dicarbazine therapy without success. I am presently on track to start a clinical trial with CTLA-4 monoclonal antibodies September 13, 2006. I have some tumors on my right side of my back and some in each lobe of my lungs. I would like to be considered for your next round of Gene Therapy in the coming months if I have no response to the CTLA-4 treatment. Please let me know if you would need a copy of my medical records to date.

Thanks again for the great work you are doing and I hope to hear from you in the near future.

Best Regards,

Jim Breitfeller

On 9/5/06 I received a call from Dr. Rosenberg’s office this morning while I was at Dr. Marino’s office. Kathy Morton (Research Nurse) contacted me by phone and asked a few questions about my health. She went on to say if I go with the CTLA-4 therapy, it would take about 2 months to washout before I could try the Gene Therapy. They would also have to do a colon biopsy to check the colon for any adverse conditions from the CTLA_4. She then gave me her direct phone number if I want to pursue the gene therapy at a later date.

So, on 9/13/06 (day 1)I had my first and only infusion of anti-CTLA-4 monoclonal antibodies. This was done as an outpatient procedure. Anti-CTLA4 monoclonal antibodies block the ability of CTLA4 to down-regulate T cell proliferation. The theory behind this therapy is that by decreasing the inhibitory signal, there will be a subsequent increase in the number of activated T-cells available, to improve the ability of the T-cells to recognize melanoma cells as non-self.

Before we can go any further, we need to know the clinical pharmacokinetics (pk)of anti-CTLA-4 monoclonal antibodies. Base on published papers, the predicted half-live of the antibody is around 3 weeks.11 This means your body will eliminate half the dose that was infused in you in about 21days. So, in 42 days or there about, the drug is completely gone from your system.

I started my CTLA-4 treatment at 9:15 am at 100 ml/hr and I had 500 mls hanging on my rack (Miss Daisy). I call the rack Miss Daisy because I have to take it with me where ever I go which includes the bathroom. I am driving Miss Daisy!! This will take us to 3:15 pm and then they draw blood for a pk study an hour later. So, we won’t get out until about 4:30 pm and home until 10:00 pm.

Day 7-9/19/06 “Along with the fatigue, my muscles ache like they have lactic acid in them”. Is this an indication of something? All immune cells begin as immature stem cells in the bone marrow.

Day 15 -9/27/06 about half the CTLA-4 antibodies are depleted. It appears that the CTLA-4 has stimulated my immune system. In the pass week, I noticed that there was redness around the area where my tumors are located. Also it is becoming quite tender in that area. This is Great news!!!!! It appears that the treatment my have kick started my immune system. The only way we will know for sure is another CT scan. That is not scheduled until November 23rd.

I sure hope this isn’t a false positive. Anyway, they gave me an antibiotic just in case it is an infection.

This inflammatory response provides a third signal that acts directly on T cells, referred to as the “danger signal”. “This signal was found to optimally activate TH1 differentiation and lead to clonal expansion of T cells12.

With this clonal expansion of the T cells and the secretion of IL-2, The Immune system is gearing up to make an assault on the foreign invaders, the tumors.

In 1988, a paper was published 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 by Itoh and Colleagues.4

In their studies, they propagated (TILs) Tumor infiltrate lymphocytes cells from 12 Metastatic Melanoma patients. They preformed kinetic growth studies in IL-2 and even broke it down three Surface markers (CD3,CD4 and CD8). The results are as follows:

The average maximum propagation was 43 days. (N=12)
The average maximum propagation for (lung, Axilla) was 40 days (n=3)
The average maximum propagation for (CD3) was 78 +/- 11 days (n=12)
The average maximum propagation for (CD4) was 33 +/- 10 days (n=12)
The average maximum propagation for CD4 (lung, Axilla) was 26 days (n=3)
The average maximum propagation for (CD8) was 49 +/- 17 days (n=12)
The average maximum propagation for CD8 (lung, Axilla) was 57 days (n=3)

Base on the above data, it would take about 49 days for my activated T cells to reach maximum propagation.

4. 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


11. H. F. Wang1, J. M. Lovering1, R. M. Shepard1, D. Zhang2, T. A. Smolarek1, J. W. Findlay3 1Pfizer Inc, 2FDA, 3Gilead Sciences Inc; Pharmacokinetics of Tremelimumab, a Cytotoxic T Lymphocyte-Associated Antigen 4 (Ctla4) Blocking Monoclonal Antibody, in Nonhuman Primates
http://www.aapsj.org/abstracts/NBC_2008/NBC08-000658.PDF

12. Holger N. Lode,1 Rong Xiang,1 Ursula Pertl,1 Elisabeth Förster,2 Stephen P. Schoenberger,3 Stephen D. Gillies,4 and Ralph A. Reisfeld1; 1The Scripps Research Institute, Department of Immunology, La Jolla, California, USA2University Children’s Hospital Vienna, Vienna, Austria3La Jolla Institute for Allergy and Immunology, Division of Immune Regulation, San Diego, California, USA4Lexigen Pharmaceuticals Corp., Lexington, Massachusetts, USA Melanoma immunotherapy by targeted IL-2 depends on CD4+ T-cell help mediated by CD40/CD40L interaction; J Clin Invest. 2000 June 1; 105(11): 1623–1630. doi: 10.1172/JCI9177 http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=300854#B13#B13



To be continued!!!!!!



Jimmy B