The long range goal of our studies is to generate durable CD8+ T cell responses against epithelial ovarian cancer (EOC) for extending remission rates. We have demonstrated a role for the immunoregulatory enzyme, indoleamine 2,3 dioxygenase (IDO) in restricting effector CD8+ expansion and augmenting expansion of CD4+CD25+FOXP3+Treg cells in human and murine ovarian cancer. In turn, we have shown that Treg cells suppress polyfunctional high avidity effector T cells derived from vaccinated patients. Consequently, we hypothesize that blockade of IDO activity by a novel IDO inhibitor, INCB024360 will (i) abrogate differentiation of CD4+ T cells into Treg cells, (ii) reverse IDO mediated arrest of T cell proliferation, (iii) unmask vaccine induced high avidity polyfunctional effector CD8+ T cells and thereby potentiate vaccine efficacy against EOC in a clinical trial. To test our hypotheses, we propose: SA1 To test whether the combinatorial regimen of IDO inhibition and rCNP-NY-ESO-1/TRICOM immunization is safe, and produces clinical efficacy in a phase I/IIb trial; SA2: To test whether INCB024360 mediated IDO blockade favors generation of high avidity polyfunctional effector CD8+ T cells; SA3: To determine the impact of IDO blockade on vaccine induced CD4+ T cell response for high avidity CD8+ Effector/Memory generation. The experimental plan is designed to test whether vaccine efficacy will be enhanced by blocking IDO mediated immune tolerance in a clinical trial. Mechanistically, because our phase II study design is randomized with a 2X2 factorial design, we will be able to delineate the impact of IDO blockade on promoting vaccine induced T cell clonal expansion and effector/memory differentiation, and whether this is mediated by relieving inhibition of high avidity polyfunctional antigen specific T cells by Tregs. The successful completion of our proposed studies will result in the generation of critical data that will facilitate Phase III evaluation of IDO blockade to relieve Treg mediated immune tolerance, promote conditions that favor durable host immunity and prolong disease free survival in ovarian cancer patients.
The goal of this project is to optimize and test a multi-modal approach consisting of vaccine therapy and blockade of IDO enzyme activity, which promotes accumulation regulatory T cells (Tregs) in ovarian cancer. This approach would greatly enhance the anti-tumor efficacy of the vaccination and potentially prolong the duration of remission in ovarian cancer patients who are in second remission.
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