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


References

1. Living Medical Textbook “Oncology” From Projects In Knowledge Contributing Writers: F. Stephen Hodi, MD and Lauren Cerruto http://www.livingmedicaltextbook.org/Activity/index.cfm?showfile=b&jn=1843&sj=1843.01&sc=1843.01.4

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 http://www.livingmedicaltextbook.org/Activity/index.cfm?showfile=b&jn=1843&sj=1843.04&sc=1843.04.2

6. http://www.glgroup.com/News/CTLA4-Blockade-in-Melanoma--Where-Next--23639.html



Jimmy B