Inhibition of indole-amine 2,3 dioxygenase to Enhance Ovarian Tumor Immunity

我们研究的长期目标是产生持久的CD8+ T细胞对上皮性卵巢癌（EOC）的反应，以延长缓解率。我们已经证明免疫调节酶，吲哚胺2,3双加氧酶（IDO）在人类和小鼠卵巢癌中限制效应CD8+扩增和增强CD4+CD25+FOXP3+Treg细胞扩增中的作用。反过来，我们已经证明Treg细胞抑制来自接种疫苗患者的多功能高贪婪效应T细胞。因此，我们假设通过一种新的IDO抑制剂INCB024360阻断IDO活性将(i)消除CD4+ T细胞向Treg细胞的分化，（ii）逆转IDO介导的T细胞增殖阻滞，（iii）揭示疫苗诱导的高活性多功能效应CD8+ T细胞，从而在临床试验中增强疫苗对EOC的疗效。为了验证我们的假设，我们提出：为了验证IDO抑制和rCNP-NY-ESO-1/TRICOM免疫联合方案是否安全，并在I/IIb期试验中产生临床疗效；SA2：检测INCB024360介导的IDO阻断是否有利于高亲和性多功能效应CD8+ T细胞的产生；SA3：确定IDO阻断对疫苗诱导CD4+ T细胞对CD8+效应/记忆产生的高亲和性反应的影响。该实验计划旨在在临床试验中测试阻断IDO介导的免疫耐受是否会增强疫苗效力。在机制上，由于我们的II期研究设计是随机的，采用2X2析因设计，我们将能够描述IDO阻断对促进疫苗诱导的T细胞克隆扩增和效应/记忆分化的影响，以及这是否通过缓解Tregs对高亲和性多功能抗原特异性T细胞的抑制来介导。我们所提出的研究的成功完成将产生关键数据，这些数据将促进IDO阻断的III期评估，以减轻Treg介导的免疫耐受，促进有利于持久宿主免疫的条件，延长卵巢癌患者的无病生存期。

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.