Synergism of anti-CTLA-4 Blockage & Depletion of CD25 Tregs Cells Melanoma.. Jim Breitfeller

Synergism of Cytotoxic T Lymphocyte–associated Antigen 4
Blockade and Depletion of CD25 Regulatory T Cells in
Antitumor Therapy Reveals Alternative Pathways for Suppression of Autoreactive Cytotoxic T Lymphocyte (CTL) Responses

Roger P.M. Sutmuller,1 Leonie M. van Duivenvoorde,1 Andrea van Elsas,1
Ton N.M. Schumacher,2Manon E. Wildenberg,1James P. Allison,3 Rene E.M.Toes,1 Rienk Offringa,1 and Cornelis J.M. Melief 1

1 Department of Immunohematology and Blood Transfusion, Tumor Immunology Lab, E3-Q, Leiden
University Medical Center, 2300 RC Leiden, Netherland

2Division of Immunology, The Netherlands Cancer Institute, 1066 CX Amsterdam, Netherlands

3 Howard Hughes Medical Research Institute, Cancer Research Laboratory, Department of Molecular and Cellular Biology, University of California at Berkeley, Berkeley, CA 94720

Abstract:

Therapeutic efficacy of a tumor cell–based vaccine against experimental B16 melanoma requires the disruption of either of two immunoregulatory mechanisms that control autoreactive T cell responses: the cytotoxic T lymphocyte–associated antigen (CTLA)-4 pathway or the
CD25+ regulatory T (Treg) cells. Combination of CTLA-4 blockade and depletion of CD25+ Treg cells results in maximal tumor rejection. Efficacy of the antitumor therapy correlates with the extent of autoimmune skin depigmentation as well as with the frequency of tyrosinaserelated protein 2 180–188 –specific CTLs detected in the periphery. Furthermore, tumor rejection is dependent on the CD8+ T cell subset. Our data demonstrate that the CTL response against melanoma antigens is an important component of the therapeutic antitumor response and that the reactivity of these CTLs can be augmented through interference with immunoregulatory mechanisms. The synergism in the effects of CTLA-4 blockade and depletion of CD25+ Treg cells indicates that CD25+ Treg cells and CTLA-4 signaling represent two alternative pathways for suppression of autoreactive T cell immunity. Simultaneous intervention with both ris therefore a promising concept for the induction of therapeutic antitumor immunity."

I contacted Dr. Roger P.M. Sutmuller from the Netherlands because I knew that in My therapy, I somehow overcame the T-Reg cells that surpress the immune response. In his research, he and colleagues had found out that if you deplete the T-Regs, it enhanced the immune response. So I took this one step further and noticed that if you delayed the addition of IL-2 after the CD4+T cell activation, we also overcame the Treg supression. The is due to a Novel Mechanism call Indexation. The Tregs (CD4+CD25+ Regulatory T cells) are indexed to the number of IL-2 producing cells. This Means that their proagation is tied to the secretion of IL-2 during the expansion of the CD4+ T cells. IL-2 is the rate limiting factor. So if you delay the addition of IL-2, then you contol the Tregs.
Neat!!!!!!

So Lets go back to The infamous Chart.


In the bottom chart you can see the IL-2 addition took place at the CD8+ T cell maximum propagation not at the cd4+ T-cell Maximum. So we controlled the propagation of the T Regs and in the process helped the CD4+,CD8+ activation to generate the Immune response.


Jimmy B