Advancing T cell Therapy for Ovarian Cancer

我们早期的研究发现，上皮性卵巢癌（EOC）是由宿主的免疫反应， 抗肿瘤免疫反应的激活与更长的生存期有关，重新燃起了免疫应答的希望。 干预可能为EOC提供重要的治疗机会。然而，目前的免疫疗法 这些方法通常没有足够的能力来诱导快速的和温/热的肿瘤排斥反应。 在过去的SPORE资助周期中，Coukos博士，June和同事们推出了一项临床研究， 卵巢癌的免疫治疗计划，在理解机制方面取得了重要进展， 禁用或减弱肿瘤免疫攻击，并开发工具来抵消这些。我们发现 肿瘤浸润淋巴细胞识别自体肿瘤，一旦适当地离体扩增， 可以抑制过继转移后的体内肿瘤生长。我们建议检验中心假设 现在有可能第一次为卵巢癌提供强大的免疫疗法， 通过先进的培养平台，我们优化了肿瘤浸润淋巴细胞（TIL）的过继治疗， 开发一个相关的假设是，现在有可能通过以下方式打破肿瘤对免疫攻击的屏障： (a)通过合理使用T细胞恢复肿瘤抗原呈递和肿瘤识别（信号1）， 化疗;和（B）恢复肿瘤部位T细胞的共刺激活化（信号2）， 用针对肿瘤抗原重定向的共刺激嵌合免疫受体（CIR）工程化T细胞。 特定目标1将把实验室结果转化为过继性淋巴细胞治疗试验。I/II期临床 将进行一项试验来检验这一假设，即适当的TIL和宿主的离体共刺激 淋巴细胞清除增加了对过继性T细胞转移疗法的应答。具体目标2建议， 通过使用化疗最大化T细胞对肿瘤的识别（信号1）。我们将测试临床前 联合过继性TIL治疗与聚乙二醇脂质体阿霉素（Doxil）的效果，并确定最佳 时间表，以便移动到诊所的组合试验。具体目标3建议最大化体内 共刺激（信号2）通过使用嵌合免疫受体。我们将测试 肿瘤来源的T细胞，其离体工程化以表达识别肿瘤细胞的共刺激嵌合免疫受体。 常见EOC抗原间皮素。 相关性（参见说明）： 目前的免疫治疗方法通常不足以诱导快速和强烈的免疫应答。 肿瘤排斥反应我们断言，先进的T细胞生产技术和 提出的药理学和工程干预措施有望解决目前的许多问题， 免疫治疗的局限性。如果我们成功了，我们的工作将产生显著的治疗增量 并为其他肿瘤提供了重要技术。

Our earlier findings that epithelial ovarian cancer (EOC) is recognized by the host's immune response, and that activation of antitumor immune response is associated with longer survival, revive hopes that immune interventions might offer important therapeutic opportunities in EOC. However, current immune therapy approaches have generally insufficient power to induce rapid and oven/vhelming tumor rejection response. Over the past SPORE funding cycle, Drs Coukos, June and colleagues have launched a clinical immunotherapy program in ovarian cancer, made important advances in understanding mechanisms that disable or attenuate tumor immune attack, and developed tools to counteract these. We have found that tumor-infiltrating lymphocytes recognize autologous tumor and once expanded appropriately ex vivo, they can suppress tumor growth in vivo following adoptive transfer. We propose to test the central hvpothesis that it is now possible for the first time to deliver powerful immunotherapy for ovarian cancer capitalizing on tumor-infiltrating lymphocytes (TIL) optimized for adoptive therapy through advanced culture platforms we developed. A related hypothesis is that it is now possible to break the tumor barriers to immune attack by (a) restoring tumor antigen presentation and tumor recognition by T cells (Signal 1) through rational use of chemotherapy; and (b) restoring costimulatory activation of T cells at the tumor site (Signal 2) through engineering T cells with costimulatory chimeric immunoreceptors (CIRs) redirected against tumor antigens. Specific Aim 1 will translate laboratory findings into adoptive lymphocyte therapy trials. A phase l/ll clinical trial will be conducted to test the hypothesis that appropriate costimulation ex vivo of TIL and host lymphodepletion augment the response to adoptive T cell transfer therapy. Specific Aim 2 proposes to maximize T cell recognition of tumor (Signal 1) through use of chemotherapy. We will test the preclinical effect of combining adoptive TIL therapy with pegylated liposomal doxorubicin (Doxil) and define optimal schedules in order to move to the clinic a combination trial. Specific Aim 3 proposes to maximize in vivo costimulation (Signal 2) through the use of chimeric immunoreceptors. We will test the preclinical efficacy of tumor-derived T cells engineered ex vivo to express costimulatory chimeric immunoreceptors recognizing a common EOC antigen, mesothelin. RELEVANCE (See instructions): Current immune therapy approaches have generally insufficient power to induce rapid and ovenwhelming tumor rejection response. We assert that the advanced techniques for T cell production and pharmacologic and engineering interventions proposed are poised to resolve many of the current limitations in immunotherapy. If we are successful, our work will produce significant therapeutic increments in ovarian cancer and provide important technology for other tumors.