mTOR inhibition for generating memory T cells to enhance ovarian tumor immunity

描述(由申请人提供)：我们研究的目标是产生持久的CD8+T细胞对上皮性卵巢癌(EOC)的反应，以延长缓解率。然而，发展有效的免疫治疗的主要障碍包括：(1)不能诱导高亲和力的扩增，肿瘤抗原特异性效应CD8+T细胞；(2)缺乏肿瘤抗原特异性记忆性CD8+T细胞；(3)存在CD4+CD25+FOXP3+调节性T细胞。在以前的研究中，我们已经观察到，尽管疫苗诱导的肿瘤抗原特异性效应器CD8+T细胞可以提供肿瘤保护，但它们不能提供通常由记忆T细胞提供的持久的肿瘤免疫。我们还注意到，雷帕霉素介导的哺乳动物靶向雷帕霉素(MTOR)的抑制通过调节转录因子T-bet和Eomesodermin将效应CD8+T细胞切换到记忆中。此外，在我们的小鼠模型中，在免疫后改变mTOR抑制的持续时间(0-8天、0-20天或0-40天)会产生具有不同程度1型效应功能的记忆CD8+T细胞。因此，我们假设，通过改变免疫卵巢癌患者雷帕霉素的给药方案(剂量和持续时间)，我们将产生具有不同程度效应功能的高亲和力CD8+T细胞，以维持卵巢肿瘤的持久免疫。因此，我们的目标是确定抑制mTOR的方案，即在I期临床试验中，与病毒载体免疫相结合不会产生毒性，但会产生最佳的持久CD8+T细胞反应。其次，通过改变雷帕霉素给药的时间，我们将确定mTOR抑制产生高亲和力的功能不同的记忆CD8+T细胞的机制。为了验证我们的假设，我们建议：SA1：在I期临床试验中，确定mTOR抑制方案(剂量和持续时间)，该方案与rCNP-NY-ESO-1/Tricom免疫相结合是安全的，并产生持久的CD8+T细胞反应。SA2：检测rCNP-NY-ESO-1/Tricom免疫后给予雷帕霉素方案是否产生具有不同程度效应功能和抗原亲和力的记忆性CD8+T细胞。SA3：确定雷帕霉素治疗方案对rCNP-NY-ESO-1/Tricom诱导的CD4+T细胞应答CD8+T细胞记忆生成的影响。我们建议的研究的成功完成将导致关键数据的产生，这些数据将促进对mTOR抑制的第二阶段评估，以产生高亲和力的记忆T细胞，促进有利于持久宿主免疫的条件，并延长卵巢癌患者的无病生存期。

DESCRIPTION (provided by applicant): The goal of our studies is to generate durable CD8+ T cell responses against epithelial ovarian cancer (EOC) for extending remission rates. However, major obstacles to the development of effective immunotherapy exist including (i) inability to induce expansion of high avidity, tumor-antigen specific effector CD8+ T cells (ii) lack of tumor-antigen specific memory CD8+ T cells, and (iii) presence of CD4+CD25+FOXP3+ regulatory T cells. In previous studies, we have observed that although vaccine induced tumor antigen specific effector CD8+ T cells can provide tumor protection, they do not provide durable tumor immunity, which is typically afforded by memory T cells. We have also noted that rapamycin mediated inhibition of mammalian target of rapamycin (mTOR) switches effector CD8+ T cells to memory via regulation of transcriptional factors T-bet and Eomesodermin. Moreover, in our murine model, varying the duration (0-8, 0-20 or 0-40 days) of mTOR inhibition after immunization produces memory CD8+ T cells with varying extent of type 1 effector functions. Consequently, we hypothesize that by changing the regimen (dose and duration) of rapamycin administration in immunized ovarian cancer patients, we will generate high avidity CD8+ T cells with varying extent of effector functions for durable ovarian tumor immunity. Therefore, our objectives are to determine the regimen of mTOR inhibition, that in combination with viral vector immunization does not produce toxicity but generates optimal durable CD8+ T cell responses in a phase I clinical trial. Second, by varying the timing of rapamycin administration, we will determine the mechanisms by which mTOR inhibition produces functionally distinct memory CD8+ T cells of high avidity. To test our hypotheses, we propose: SA1: To determine the regimen (dose and duration) of mTOR inhibition that in combination with rCNP-NY-ESO-1/TRICOM immunization is safe and produces durable CD8+ T cell responses in a phase I clinical trial. SA2: To test whether the regimen of rapamycin administration after rCNP-NY-ESO-1/TRICOM immunization generates memory CD8+ T cells with varying extent of effector functions and antigen avidity. SA3: To determine the impact of rapamycin treatment regime on rCNP-NY-ESO-1/TRICOM induced CD4+ T cell response for CD8+ T cell memory generation. The successful completion of our proposed studies will result in the generation of critical data that will facilitate Phase II evaluation of mTOR inhibition to generate high avidity memory T cells, promote conditions that favor durable host immunity, and prolong disease free survival in ovarian cancer patients.