IRP-3

摘要：尽管卵巢癌(OvCa)的治疗标准提高了疗效，但总体上五年 OvCa患者的存活率仅为47.6%。多克隆T细胞对多种癌症和患者的反应 特异性抗原是有效的癌症免疫和结果的关键因素。 项目3开发和测试了一种新的免疫策略，以增强细胞毒性淋巴细胞的诱导 (CTL)通过靶向肿瘤细胞、内源性树突状细胞(DC)来对抗多个患者特异性表位 和体外产生的DC。我们将对OvCa细胞和两个种群的免疫肽进行比较 专门研究CTL诱导的DC：体外产生的α-1型极化(α)DC和内源性DC 具有炎症性BATF3/IRF8表型和增强的能力的常规DC(CDC 1) 交叉递呈多种肿瘤细胞相关抗原给CD8+T细胞。 结合我们独特的体外致敏(IVS)和生物信息学方法，我们将测试整体 OvCa细胞免疫表位与树突状细胞提呈抗原不匹配的假说 限制自发和疫苗诱导的CTL的治疗效果 回应。我们进一步假设αDC 1装载了合成的患者特异性新抗原肽 将绕过这种错配，诱导CTL在杀死OvCa肿瘤方面特别有效。我们建议 以下三个目标： 特异性目的1：比较负载人CD8+T细胞的树突状细胞的抗原特异性 经鉴定的自体OvCa细胞、肿瘤洗脱肽和患者特异性新抗原肽 In-Silicon o正在接近。我们推测，自体癌细胞负载的DC1s或 CDC1含有大量与肿瘤识别无关的CTL，其缺陷可能是 通过向树突状细胞加载针对每个患者OvCa细胞的合成新抗原肽进行更正。 特异性目标2：评价OvCa细胞与荷瘤细胞免疫表位组的差异 αdc1和内源性cdc1，并检验其调节的可行性。我们假设 免疫佐剂和炎症介质可用于调节APM模式和 DC和OvCa细胞的免疫表位，以增强产生的CTL和OvCa细胞之间的抗原匹配 自体OvCa细胞。 具体目标3：确定α疫苗的可行性、安全性和临床疗效 患者特异性新抗原肽联合PD-1阻断。每位患者将接受8个疗程 携带患者特异性新抗原和培溴利珠单抗的Dc1疫苗。以AIM的结果为指导 2、患者还可接受全身免疫调节，以增加其自身卵泡的可见度 细胞向诱导CTL，减少免疫抑制。临床疗效将由iORR监测。 预期影响：项目3的结果将转化为新型治疗性疫苗的开发和 前瞻性地探索免疫检查点抑制和过继T细胞治疗的新模式。

ABSTRACT: Despite increasing efficacy for standard of care of ovarian cancer (OvCa), the overall five-year survival of OvCa patients is only 47.6%. Polyclonal T cell responses against multiple cancer- and patient- specific antigens are the key element of effective cancer immunity and resulting outcomes. Project 3 develops and tests a new immunization strategy to enhance the induction of cytotoxic lymphocytes (CTLs) against multiple patient-specific epitopes, by targeting cancer cells, endogenous dendritic cells (DCs) and ex vivo generated DCs. We will compare the immunopeptidomes on OvCa cells and two populations of DC specialized in CTL induction: ex-vivo generated alpha-type-1-polarized (αDC1s) and endogenous conventional DCs (cDC1s) which share the inflammatory BATF3/IRF8 phenotype and elevated ability to cross-present multiple cancer-cell-associated antigens to CD8+ T cells. Combining our unique in vitro sensitization (IVS) and bioinformatics approaches, we will test the overall hypothesis that the mismatch between immunopeptidomes of OvCa cells and DCs presenting antigens from cancer cells limits the therapeutic effectiveness of spontaneous and vaccination-induced CTL responses. We further hypothesize that αDC1s loaded with synthetic patient-specific neoantigen peptides will bypass such mismatch, inducing CTLs particularly effective in killing OvCa tumors. We propose the following three Aims: Specific Aim 1: Compare the antigenic specificity of human CD8+ T cells induced by DCs loaded with autologous OvCa cells, tumor-eluted peptides and patient-specific neoantigen peptides identified by in-silico approaches. We hypothesize that CTLs induced by autologous cancer cell-loaded DC1s or cDC1s contain large number of CTLs which are irrelevant for tumor recognition, which deficit can be corrected by loading DCs with synthetic neoantigen peptides specific to each patient's OvCa cells. Specific Aim 2: Evaluate the immunopeptidome differences between OvCa cells and tumor-loaded αDC1s and endogenous cDC1s and test the feasibility of their adjustment. We hypothesize that immune adjuvants and inflammatory mediators can be used to modulate APM patterns and immunopeptidomes of DCs and OvCa cells, to enhance the antigenic match between arising CTLs and autologous OvCa cells. Specific Aim 3: Determine the feasibility, safety and clinical efficacy of αDC1 vaccines loaded with patient-specific neoantigen peptides combined with PD-1 blockade. Each patient will receive 8 courses of DC1 vaccines loaded with patient-specific neoantigens and pembrolizumab. Guided by the results of Aim 2, the patients may also receive systemic immune modulation to increase the visibility of their own OvCa cells to DC1-induced CTLs and reduce immune suppression. Clinical efficacy will be monitored by iORR. Predicted Impact: Results of Project 3 will be translated into development of novel therapeutic vaccines and prospectively into new modes of immune checkpoint inhibition and adoptive T cell therapies.