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
http://cdli.highwire.org/cgi/content/full/8/4/671
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
http://jem.rupress.org/cgi/reprint/168/4/1419.pdf
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
http://www.jimmunol.org/cgi/content/full/169/4/1753
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”
http://www.jimmunol.org/cgi/content/full/169/4/1753
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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