Rapamycin and IL-21 Conditioned CD8+ T Cells for Adoptive Cellular Therapy of Ov

免疫疗法是延长卵巢癌缓解率的一个有吸引力的选择。使用体外产生的肿瘤抗原特异性效应/记忆CD8+ T细胞的过继细胞转移（ACT）绕过卵巢癌患者存在的调节环境，可以介导持久免疫。然而，体外产生效应/记忆CD8+ T细胞的策略尚未被描述，ACT在治疗卵巢肿瘤中的应用仍未经过测试。根据我们报告的发现和使用小鼠和人类T细胞产生的新证据，我们假设γ链细胞因子；IL-21联合mTOR抑制剂；雷帕霉素，将在体外产生肿瘤抗原特异性效应/记忆CD8+ T细胞，使卵巢癌患者通过ACT获得持久免疫。我们设计了两个具体的目标来检验假设，并产生可以支持第二阶段试验的信息。首先，确定产生具有高复制潜力的人类WT1特异性效应/记忆性CD8+ T细胞的最佳雷帕霉素和IL-21的组合剂量，用于过继细胞治疗；其次，在I期研究中评估IL-21/雷帕霉素条件下WT-1特异性CD8+ T细胞过继转移到晚期卵巢癌患者的安全性、体内持久性和抗肿瘤功效。本研究的完成将确定产生抗原特异性CD8+ T细胞的效应/记忆功能的新策略，并测试其在ACT中的疗效，有可能建立治疗卵巢癌的新途径。

Immunotherapy is an attractive option to extend remission rates in ovarian cancer. The use of adoptive cell transfer (ACT) of ex vivo generated tumor-antigen specific effector/memory CD8+ T cells circumvents the regulatory environment present in ovarian cancer patients and can mediate durable immunity. However, strategies to ex vivo generate effector/memory CD8+ T cells have not been described and the application of ACT to treat ovarian tumor remains untested. Based on our reported findings and new evidence generated by using both murine and human T cells, we hypothesize that the gamma chain cytokine; IL-21 in combination with mTOR inhibitor; rapamycin, will ex vivo generate tumor-antigen specific effector/memory CD8+ T cells that enable durable immunity to ovarian cancer patients by ACT. We have designed two specific aims to test the hypothesis and generate information that can support a phase 2 trial. First, to determine the combinatorial dose of Rapamycin and IL-21 that optimally produces human WT1 specific effector/memory CD8+ T cells with high replicative potential for adoptive cellular therapy and second to evaluate in a Phase I study, the safety, in vivo persistence and anti-tumor efficacy of IL-21/ Rapamycin conditioned WT-1 specific CD8+ T cells adoptively transferred to patients with advanced ovarian cancer. The completion of this study will identify a new strategy to generate antigen-specific CD8+ T cells for effector/memory function and test their efficacy in ACT, it is likely to establish a new approach to treat ovarian cancer.