Wednesday, January 14, 2009

A Reply back from DR. Markovic, Svetomir N., M.D., Ph.D. ON Emerging Therapies for Melanoma ..Jim Breitfeller

Emerging Therapies for Melanoma

Rajini Katipamula; Svetomir N Markovic
Expert Rev Anticancer Ther. 2008;8(4):553-560.
Posted 07/09/2008

Dear Mr. Breitfeller,
Thank you for your note.

I just got back from a trip and am catching up with e-mail. I must say, I really enjoyed reading your message.

Our thoughts on the matter (as summarized in my brief article you noted) are basically that there are 3 elements to the puzzle that need to be addressed:

(1) the tumor; (2) its vascular supply; and (3) the body's immune system.
Addressing each one of these alone, will only gain little benefits for most, transient benefits for some and awesome results in a lucky few patients. So, why not look at the problem in the context of the patient.

And, that is basically where we are right now. We are crafting therapies that will engage all 3 elements; we measure the impact on all 3 and gain insights into what's working, what's not, and what we need to do next.

The first study we did using this approach was just published in Cancer this month. And, we did reasonably well for the majority of patients (best progression free survival result in a single arm phase II study done by the US cooperative groups in patients with metastatic melanoma).

What was most interesting is that we learned that the drugs we used may have worked in a completely different mechanism... The combination of chemotherapy and an inhibitor of angiogenesis may have yielded the good clinical outcomes via an immunological mechanism (paper in preparation).

I think that there may be something to this, and we'll keep plugging on this path. Hopefully we will be able to lend some insights that may be helpful to our patients and colleagues.

Take care,

From: dbreitfe []
Sent: Monday, January 05, 2009 8:28 AM
To: Markovic, Svetomir N., M.D., Ph.D.
Subject: permission to post on Carepages "Emerging Therapies for Melanoma"

Svetomir, I am a cancer patient under the care of John M Kirkwood at the Hillman Cancer Center. I think you paper is very fascinating. Let me give you a little back ground of my dealings with Melanoma:

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. I asked my wife to take a look at it. It was just a mole. So I decide to go to the dermatologist. To make the log story short, it was cancer. It took about a month and a half to get it biopsied . (Sept. 26 2005) I contacted a surgical oncologist and on October 27 2005 I had a wide incision to remove the tumor off my back. I also had a PET scan and a sentinel lymph node biopsy done and it showed no cancer except the localized one on my back. 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. They all recommended to start with Interferon treatment. In the meantime, my back got infected and it took until Feb. 14 2006 to heal. On March 6 2006, I started the High Dose Interferon treatment that was to last 4 weeks with daily infusions. The treatment lasted only 2 ½ weeks because my blood sugar went completely out of control. I also have type 2 diabetes.

About 2 weeks after the interferon treatments, I noticed my right lymph node growing to golf ball size and they were aching. I had them biopsied (April 4 2006) and 9 out of 11 nodes were cancerous. On April 24th , I had my lump nodes removed under my right arm. This had move me from a stage 3 to a stage 4. The cancer was spreading quite rapidly. Strong did not have any specialists in the field of malignant melanoma. So, I was in contact with Dr. John Kirkwood in Pittsburgh. So with my oncologist approval, my wife and I went down to Pittsburgh and had a consultation with Dr. Kirkwood (June 12, 2006) Kirkwood wanted another PET scan (June 16 2006) to see if the cancer was contained to my lymph nodes. The results showed 4 tumors on my back, one under my right arm, and two spots, one in each lobe of my lungs. It wasn’t good.

So, On July 10, 2006, I started my clinical trial of Dicarbazine and Patrin cycle 1. Each cycle is 21 days. On day 3, I am injected with dicarbazine at the Hillman Cancer Center in Pittsburgh. On the 11th day I go back to have a check up. Twice a month I traveled to Pittsburgh at least with this trial. I started my 2nd cycle on July 31 2006. On August 17 I had a CT scan and the report showed new tumors in my lungs so they stopped the Dicarbazine trial.

On September 6th, I had another CT scan and MRI for the next trial which was Anti-CTLA-4. On September 13 I had my first infusion. On October 8, 2006 My wife noticed two new growths on my back. It was confirmed on October 11th it was new tumors.
Dr. John Kirkwood has decided that IL 2 Interlukin 2 would be next course of action. I have completed another round of tests (CT scan, Pulmonary Function, and a Nuclear Stress Test). The CT scans shows 40+ nodules in my lungs ranging from 15mm to less than 5mm.

I am slated to be High dosage IL-2 on November 1st 2006.

I am presently washed out an IL-2 clinical trial that started in November 1, 2006. On the fourth cycle I had a heart attack and the doctors determined to abort the IL-2 on February 2, 2007. On August 23 2007 there was no change to the tumors in my back or lungs but also no growth. In October 24 2007 I got the word that the tumors and the lung nodules were shrinking. In April 14, 2008, the 40 + nodules in my lungs decrease to 2. In July 2008, the nodules in my lungs were undetectable and the ones on my back were all but one gone. Presently, CT and MRI
In November 2008 show no signs cancerous activity. I am stabilized for the time being.

As you can see I did the CTLA-4, one dose and then went on to IL-2 until I had a heart attack. Base on your 5 year View, in my case, my overall survival rate has doubled so far.

“Five-year View”

“Several advances are being made in the field of immunological and targeted therapies. In our opinion, the agents of most interest in the next 5 years would be the anti-CTLA-4 antibodies and angiogenesis inhibitors combined with cytotoxic therapy. While most of these novel agents may not have significant single-agent activity, combining them with systemic chemotherapy might be the key to clinical success in melanoma. Ultimately, rational combination therapeutics of multimodal targeting agents (immunotherapeutics, cytotoxic therapy, angiogenesis inhibitors) will likely lead to substantive clinical benefit in this patient population. Our hope is that this massive clinical research endeavor will soon yield the long sought after improvement in the overall survival of patients with advanced melanoma.”

Being a researcher myself, I came up with a theory.

11/06/08 This is my Theory
Posted Nov 6, 2008 9:59am

11/06/08 This is my Theory
The Interlukin-2
IL-2, which works by stimulating killer T-cells to attack melanoma. In some cases with the right body chemistry, helps communicate that message to the killer T-cells and the body begins to fight off the Beast.

In other cases, your body chemistry is different than mine and may lack some sort protein/? or what ever. So in this case, the communication is lost like a drop signal from your cell phone. What you need is another Cell Tower to transmit that signal. That is where CTLA-4 coming in to play. It builds the tower to help with the communication. I may be over simplifying the biochemistry but I am not in the lab to do the right experiments. So, I have to take an educated guess.

So, I did a little online research

As you can see, Dr. Kirkwood and I wanted to induce tumor regression by using my own immune system. If we could get my immune system to recognize the tumors as foreign, then we might have a fighting chance.

So we decide to try the CTLA-4 Therapy, Antitumor response with prolonged time to progression has been seen in patients with melanoma who have received either of the CTLA-4 antibodies and durable antitumor responses have been observed with ipilimumab in patients with melanoma ovarian cancer, prostate cancer, and renal cell carcinoma It has been seen, antitumor responses may be characterized by short-term progression followed by delayed regression.

An important, possibly unique, clinical characteristic of anti-CTLA-4 antibodies is that the duration of clinical response -- and even stable disease -- is often quite prolonged.

This is what I believe is going on in my case but I have no proof.

So lets combine the two clinical trials and that was done by Dr. Rosenberg at the National Cancer Institute. This did not yield the Better outcome.

I think it is because doing the therapy at the same time my be jamming the signals or changing the micro-chemical in the cell and surrounding environment so that it is not inductive to passing on the communication cell to cell.. protein to protein .

But since there was a lag between my two therapies, My cells began to communicate and jump started my immune system. Do I think is a one off, NO!!!!! I have been in touch with another patient that did IL-2 then, CTLA-4 and got the same response. The trick is to get the timing and the dose right!!!!!

So I took it apon myself to to a little research and this is what I came up with. I believe it all makes sense. I still may be over simplifying the actual process but I am not a biochemist. So Here goes:

Dendritic cells (DCs) are immune cells and form part of the our immune system. Their main function is to process antigen material and present it on the surface to other cells of the immune system, thus functioning as Antigen-Presenting Cells (APC).
The dendritic cells are constantly in communication with other cells in the body. This communication can take the form of direct cell-to-cell contact based on the interaction of cell-surface proteins. An example of this includes the interaction of the receptor B7 of the dendritic cell with CD28 present on the lymphocyte. However, the cell-cell interaction can also take place at a distance via cytokines. These components of the immune system communicate with one another by exchanging chemical messengers. These proteins are secreted by cells and act on other cells to coordinate an appropriate immune response.

Cytokines include a diverse assortment of interleukins, interferons, and growth factors.One cytokine, interleukin 2 (IL-2), triggers the immune system to produce T cells. IL-2’s immunity-boosting properties have traditionally made it a promising treatment for several illnesses which include Hepatitis C and Melanoma.

There are several steps to activation of the immune system against a foreign molecule. The T cell receptor must first interact with the MHC molecule. The T cell receptor or TCR is a molecule found on the surface of T lymphocytes (or T cells) that is, in general, responsible for recognizing antigens bound to Major Histocompatibility Complex (MHC) molecules. MHC the most gene-dense region of the Human genome and plays an important role in the immune system, autoimmunity.

This first interaction involves the CD4 or CD8 proteins which form a complex with the CD3 protein to bind to the MHC molecule of the (APC). Antigen-presenting cell This is also called "Signal 1" and its main purpose is T cell activation.

However, this is insufficient for producing a T cell response by itself. In fact, lack of further stimulatory signals sends the T cell into anergy. Anergy is a term in immunobiology that describes a lack of reaction by the body's defense mechanisms to foreign substances.

The Second costimulatory signal necessary to continue the immune response can come from B7-CD28 and CD40-CD40L interactions. The primary role of the B7 proteins is to give a second signal to the T cell. The B7 protein/receptor is present on the Antigen-presenting cell and is able to interact with the CD28 receptor on the T cell surface; this is also known as "Signal 2". There are other activation signals which play a role in immune responses.

On these T cells there is are family receptors whose job is downregulate the T cell activation so the immune system maintains metabolic equilibrium so the immune system doesn’t start an autoimmune response and cause it to attack itself. One of these receptors is Cytotoxic T lymphocyte-associated antigen (CTLA4).

It was hypothesized back in the 1980’s that if you replaced the CTLA4 with Anti-CTLA4 that it might block the B7 receptor causing an enhancement of the T-cell activation, leading to a more robust antitumor immune response.

It was shown in mice with a disrupted CTLA-4 genes that their immune response ran unabated causing autoimmunity which was fatal.

It was also shown that the anti-CTLA-4 antibodies had a greater affinity to CTLA-4 than the B7 receptor. So by doing the CTLA-4 Therapy, it allowed signal 1 to become active.

So in the presents of the CTLA-4 antibody Therapy, I my case, we may have extended the antitumor response of the T-cells. This left Signal 1 active.

We then, hit the immune system with High dose of IL-2. This must have stimulated the cell to cell communication (Signal 2) causing the immune response to kick in against the foreign molecule (The Tumor)


Just don't know how long it will last.

AS you can see , I am passionate about finding a cure. My Life depends on it. So if I can pass along information that may help others, I do. And that is why I am asking for your Permission on post this information.

I hope to here from you soon

Thanks for your time and Keep the good research coming!!!!


James M. Breitfeller

The information contained is intended for the confidential use of the intended recipient(s) only and may be legally privileged. If it has been received other than by an intended recipient, it may not be reviewed, disseminated, distributed, copied or retained. Therefore, please notify the sender immediately and delete the original message and all copies.

Thank you

James M. Breitfeller

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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 " : 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.