Monday, February 9, 2009

Did the clinical trials on CTLA-4 Therapy Sell us short and we missed the boat??..Melanoma.. Jim Breitfeller

My experience with CTLA-4 Blockage Therapy:

On 9-13-2006 I received my first and only dose of CTLA-4.

9-19-2006 – “The New CTLA-4 trial, has sent me for a loop. I wake up exhausted. I have to push myself to get out of bed. Along with the fatigue, my muscles ache like they have lactic acid in them. Well, no pain no gain.”

9/27/06—“Saw the Physician Assistant, Melissa. 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 29th .

Oct 10, 2006—“I still have fatigue but I am managing it. What really bothers me is my right arm where they removed the lymph nodes. I can't get the swelling down which in turn puts pressure on my nerves. I have to baby it to try to bring down the swelling. Some days it feels like it is caught in a vise. I am going ask if they can drain the excess fluid if possible.”

Oct 12, 2006—“A couple of days ago, Dee noticed two new growths on my back. I was hoping for the best. Anyway, we got confirmation from the Hillman Center that it is 2 new tumors growing. This really stinks. I think it is time to take out the “Weed be Gone”. This is not what I was hoping to hear.” The therapy with CTLA-4 was terminated”.
“So, it is on to the next trial. I am not sure what is going to be, but they mention Interleukin -2.”

“Improved understanding of the functions of CTLA-4 led to the hypothesis that blocking its engagement could result in unopposed CD28 activation of T-cells coupled with suppression or depletion of regulatory cells. In essence, blockade of CTLA-4 leads to "taking the brakes off" the immune system.”1

Antitumor activity has been observed in melanoma after treatment with anti-CTLA-4 antibodies, as well as the potential for autoimmune-related toxicities. The Anti-CTLA-4 antibodies would bind to the B7 receptor. This in turn would keep the T-Cells activated for a prolonged time.

“It has been seen that CTLA-4 antibody blockade alone has had minimal effects in other mouse tumors, however, including the poorly immunogenic B16 melanoma2 and SM1 breast cancer.3 However, the combination of CTLA-4 blockade and vaccination with GVAX (irradiated tumor cells engineered to secrete cytokine granulocyte-macrophage colony-stimulating factor [GM-CSF]) resulted in significant tumor regression in B16 melanoma.2

The immune system is a powerful weapon, and the body does not use it lightly. Cells in this system must all be activated before they can begin proliferating and carrying out their instructions. For T-cells, two steps are required for activation. This safeguard can be likened to the two keys needed to open safe deposit boxes, in which the box holder has a key unique to that box, and the bank teller has a key that fits all boxes, but both keys are needed to open any particular box.4

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. IL-2 aids in the “Cell to Cell” communication.

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). So Using the CTLA-4 blockade, the two keys are there to produce the wanted immune response which is to attack the foreign molecule (The Tumor)

Tremelimumab and ipilimumab, two fully human Monoclonal Antibodies (mAbs) that block CTLA-4, have progressed into clinical trials and demonstrated antitumor activity in cancer patients. Most clinical investigations have been performed in patients with advanced melanoma .

In looking at Phase 1 and Phase 2 Clinical trials:

Table 1. Phase I and II Clinical Trials of CTLA-4 Blockade in Metastatic Melanoma5

In the Living Medical Textbook “Oncology” Chapter 4 and looking at the Efficacy Data, I notice that Dr. Maker had the best (CR) complete response 8%.

“Tumor Regression and Autoimmunity in Patients Treated With Cytotoxic T Lymphocyte–Associated Antigen 4 Blockade and Interleukin 2: A Phase I/II Study

The way I derived the percentage was to take the number of complete responses and divide it by the number of patients in the trial, times 100. I also noticed that most of the complete responses were with a combination / additional therapy. This is SCREAMING OUT that this agent needs to be done in combination with other agents.

When Pfizer did there phase three trial against dacarbizine, the trial was done as a single agent. “Pfizer's randomized phase III of tremelimumab versus the fool's gold standard dacarabzine/DTIC was stopped due to futility.”6

I believe that CTLA4 blockade has clinically significant activity in melanoma and that we need to come back and address how to use this agent in combination with other agents.

I know that Dr. Rosenberg has tried with IL-2 and saw no additive improvement. I believe the trial was flawed in that the dosing was given at the same time.

“We have just not learned how to use these drugs to their maximum effect. Strategies that focus on complementary combinations intended to increase their immunostimulatory effect seem to be the right path. I just hope that we will not abandon CTLA4 blockade based merely on results of protocols that were not fair assessments of their possible activity”6

I am an example of the right Protocol:

“On September 6th, I had another CT scan and MRI for the next trial which was Anti-CTLA-4 Blockage . 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 Interleukin 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 did one cycle of CTLA-4, during that time I notice that there was redness around the tumor area and was soar. At the time we (the physician assistant) thought it was an infection. In retrospect, it was the activation on my T cells. Two new tumors appeared and it was decided to go on to interleukin-2 (High dose). Well , I believed that the IL-2 started the cell to cell communication, which was the costimulant to the T cell and there my immune system began the assault on the foreign invaders (the tumors).

I have seen this with another patient but did the IL-2 first with no success. But then went on to the CTLA-4 therapy and the tumors shrank.

I believe we are on to some thing big!!!!!!!!!! We must Investigate this combination therapy.

Jimmy B


1. Living Medical Textbook “Oncology” From Projects In Knowledge Contributing Writers: F. Stephen Hodi, MD and Lauren Cerruto

2. Van Elsas A, Hurwitz AA, Allison JP. Combination immunotherapy of B16 melanoma using anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and granulocyte/macrophage colony-stimulating factor (GM-CSF)-producing vaccines induces rejection of subcutaneous and metastatic tumors accompanied by autoimmune depigmentation. J Exp Med. 1999;190:355-366.

3. Hurwitz AA, Yu T F-Y, Leach DR, Allison JP. CTLA-4 blockade synergizes with tumor-derived granulocyte-macrophage colony-stimulating factor for treatment of an experimentral mammary carcinoma. Proc Natl Acad Sci U S A. 1998;95:10067-10071.

4. Sompayrac L. How the Immune System Works. 3rd ed. Malden, MA: Blackwell Publishing; 2008

5. Table 1. Phase I and II Clinical Trials of CTLA-4 Blockade in Metastatic Melanoma5


Jimmy B

No comments:

Post a Comment

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.