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。体外产生的肿瘤抗原特异性效应/记忆性CD8+T细胞的过继细胞转移(ACT)的使用绕过了卵巢癌患者存在的调节环境，并可以介导持久免疫。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得到测试。基于我们已报道的发现和使用小鼠和人类T细胞产生的新证据，我们假设伽玛链细胞因子IL-21与mTOR抑制剂雷帕霉素联合使用，将在体外产生肿瘤抗原特异性效应/记忆CD8+T细胞，从而通过ACT对卵巢癌患者进行持久免疫。我们设计了两个特定的目标来检验假设并产生支持第二阶段试验的信息。首先，确定雷帕霉素和IL-21的组合剂量，以最佳地产生具有高复制潜能的人WT1特异性效应/记忆性CD8+T细胞用于过继细胞治疗；第二，在I期研究中，评价IL-21/雷帕霉素调节的WT-1特异性CD8+T细胞过继转移给晚期卵巢癌患者的安全性、体内持久性和抗肿瘤效果。这项研究的完成将确定一种新的策略来产生抗原特异性的CD8+T细胞来实现效应/记忆功能，并测试其在ACT中的疗效，这可能为卵巢癌的治疗开辟一条新的途径。

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.