Tuesday, March 24, 2009

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

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


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


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”


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

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Greetings to One and All

This Blog is dedicated My Brother Kenny B. who passed away in the late 1970's with Cancer before the Internet.

It was he, who showed me How to live and give back. He was wise beyond his years.

Kenny B

Jimmy and Dee

Carepage: Jimmybreitfeller
Jimmy Breitfeller

My Profile as of 2009

My photo
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 long story short, it was cancer. I knew from my research that I would be needing adjuvant therapy. So I started communicating with Sloan Kettering, University of Pittsburgh Cancer Center, and a couple of others including the Wilmot Cancer Center at Strong. I realized that by telling my story, I might help someone else out there in a similar situation. So to all who are linked by diagnosis or by relation to someone with melanoma, I wish you well. Stay positive, read as much as you can (information helps to eliminate the fear associated with the unknown), and live for today, as no one can predict what tomorrow may bring. Jimmy B. posted 12/15/08


The information contained within this Blog is not meant to replace the examination or advice of your Oncologist or Medical Team. The educational material that is covered here or Linked to, does not cover every detail of each disorder discussed.

Only your physician/Oncologist can make medical decisions and treatment plans that are appropriate for you. But, An Educated Consumer is a Smart consumer.

As Dr. Casey Culberson Said:

"The BEST melanoma patient is an ACTIVE PARTICIPANT in his or her treatment

Melanoma and the “Magic Bullet” (Monoclonal Antibodies)

Just to let you know I posted the first draft of the Melanoma and the “Magic Bullet” (Monoclonal Antibodies). on Melanoma Missionary In the Shared File Section. you can download it for 19.95 (Only kidding) it is Free for the taking.

It is 33 pages long and may help you in your quest for the Yellow Brick Broad. Just to let you know it is only the first draft. Revisions are sure to come. I wanted to get it to the people that need it the most, the Melanoma Patients.


So, where does Interluekin-2 (IL-2) come into play? According to Byung-Scok et al and recent reports, IL-2 is not needed for developmental CD4+ CD25+ Treg cells in the thymus but does play an important role in the maintenance and function in the peripheral.18 Peripheral is defines as secondary system outside the bone marrow and thymus. It entails the site of antigen, immune system interaction. IL-2 is required for the peripheral generation of Tregs based Abbas’s and colleagues research.19

IL-2 prevents the spontaneous apoptosis of the CD4+ CD25+ Treg cells. It has been reported that patients with multiple advance-stage tumors have elevated levels of Tregs within the tumor microenviroment.20 Interluekin-2 is the survival factor for CD4+ CD25+ Treg cells.21 If the addition of IL-2 is on or before the maximum propagation of the CD4+ T cells, the Tregs population can increase 5-fold in a 96 hour period based on certain growth mediums.

By controlling the addition of the endogenous IL-2, one has a knob to turn and can lead to the control of the expansion of the Tregs. When you combined this control with the anti-CTLA-4 blockage, you can shift the balance of the immune response.

Now here is the catch. The maintenance and function of the CD8+ T-cells require CD4+ cells which secrete IL-2. So we don’t want to deplete the CD4+ cells, we want to control the expansion of the Tregs which are a subset of the CD4+ cells. It has been postulated by some researchers that the Anti-CTLA-4 blockage also suppresses the Treg function in a different mechanism. By using IL-2 as the rate limiting factor, we can suppress the CD4+ CD25+ Treg cell expansion by controlling the concentration and timing of the Inerluekin-2 at the tumor microenvironment.

The Interluekin-2 plays another role in this Melanoma Maze. In a study by Janas et al, Il-2 increases the expressions of the perforin and granzyme A, B and C genes in the CD8+ T-cells. This increase expression causes the CD8+ T-cells to mature into Cytoxic T Lymphocytes (CTLs). The exogenous IL-2 is required for the granzyme proteins. As stated previously, CTLs have cytoplasmic granules that contain the proteins perforin and granzymes. A dozen or more perforin molecules insert themselves into the plasma membrane of target cells forming a pore that enables granzymes to enter the cell. Once in the tumor cell, these enzymes are able to breakup (lyse) the cell and destroy it. This is the beginning of the end for the cancer cells. The tumors begin to shrink and the rest is history,

On the other hand, prolong therapy with Il-2 can result in causing apoptotic death of the tumor- specific CD8+ T-cells.23

Clearly in a clinical setting, timing, dose, and exposure to these drugs play a major roll in the immunotherapy, and can have dramatic effects on the outcome.

All it takes is that one magic bullet to start the immune reaction..


Melanoma And The Magic Bullet (Monoclonal Antibodies)

Public Service Announcement

A call for Melanoma Patients by Dr. Steven A Rosenberg

"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

For the Warriors

The Melanoma Research Alliance has partnered with Bruce Springsteen, the E Street Band, and the Federici family to alleviate suffering and death from melanoma. Please view Bruce Springsteen’s public service announcement inspired by Danny Federici. Danny was the E Street Band’s organist and keyboard player. He died on April 17, 2008 at Memorial Sloan-Kettering Cancer Center in New York City after a three year battle with melanoma.


Source Fastcures blog

Join the Relay for Life!!!


Dear Family and Friends,

I’ve decided to take a stand and fight back against cancer by participating in the American Cancer Society Relay For Life® event right here in my community! Please support me in this important cause by making a secure, tax-deductible donation online using the link below.

To donate on line now, click here to visit my personal page.
Jimmy B AKA Melanoma_Missionary

Relay For Life® is a life-changing event that brings together more than 3.5 million people worldwide to:

CELEBRATE the lives of those who have battled cancer. The strength of survivors inspires others to continue to fight.

REMEMBER loved ones lost to the disease. At Relay, people who have walked alongside people battling cancer can grieve and find healing.

FIGHT BACK. We Relay because we have been touched by cancer and desperately want to put an end to the disease.

Whatever you can give will help - it all adds up! I greatly appreciate your support and will keep you posted on my progress.

Keep the Fire Burning!!!



Jimmy Breitfeller
Turn off Music before you "Click to Play"
Signs of Melanoma Carcinoma Skin Cancer

How Skin Cancer Develops by "About.com : Dermatology"

Call for Patients with Unresectable Liver Metastases Due to Melanoma

Delcath Systems Granted Orphan-Drug Designations for Cutaneous and Ocular Melanoma

Delcath is actively enrolling patients in a Phase III clinical trial testing its proprietary drug delivery system, known as Percutaneous Hepatic Perfusion (“PHP”), with melphalan for the treatment of ocular and cutaneous melanoma metastatic to the liver.

This NCI-led trial is enrolling patients at leading cancer centers throughout the United States. Commenting on these orphan-drug designations, Richard L. Taney, President and CEO of Delcath, stated, “These favorable designations are important steps in our efforts to secure Delcath’s commercial position upon conclusion of our pivotal Phase III trial for metastatic melanoma. We remain steadfast in our commitment to become the leader in the regional treatment of liver cancers and we continue to enroll patients in this study, and advance our technology and the promise that it offers to patients with these deadly forms of melanoma and other cancers of the liver, all with limited treatment options.”

Orphan drug designation, when granted by the FDA’s Office of Orphan Products Development, allows for up to seven years of market exclusivity upon FDA approval, as well as clinical study incentives, study design assistance, waivers of certain FDA user fees, and potential tax credits.

Current Trial Centers

Phase I Study of Hepatic Arterial Melphalan Infusion and Hepatic Venous Hemofiltration Using
Percutaneously Placed Catheters in Patients With Unresectable Hepatic Malignancies

James F. Pingpank, Jr., MD, FACS
Associate Professor of Surgery
Division of Surgical Oncology
Suite 406, UPMC Cancer Pavillion
5150 Centre Avenue
Pittsburgh, PA 15232
412-692-2852 (Office)
412-692-2520 (Fax)

Blog Archive

Call For Melanoma Patients!!!!

Call For Melanoma Patients!!!!

Dr. Rosenberg Has a New Clinical Trial.

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

Dr. Rosenberg's Clinical Trials

(For a copy of the research paper.. see My Shared files)

The news headlines shown above for Melanoma / Skin Cancer are provided courtesy of Medical News Today.