Neoantigen immunotherapy in brain tumors using anti-CD27 to deplete regulatory T cells selectively

摘要-项目1 在像胶质母细胞瘤(GBM)这样的脑瘤中，未能开发出有效的疫苗和实现免疫 检查点抑制被归因于显著的免疫抑制和非同寻常的 抗原性肿瘤内异质性。GbM免疫抑制的一个主要原因是调节性升高。 显著抑制T细胞效应功能并降低抗肿瘤疗效的T细胞(Tregs) 接种疫苗。通过靶向白细胞介素2受体α(CD25)来耗尽Treg的努力没有成功 由于对效应性T细胞的细胞毒作用，这是促进抗肿瘤免疫所必需的。至 克服这一障碍，项目1建立了新的初步数据，证明了临床上可用的 CD27激动型抗体(αCD27)同时清除Treg和增强疫苗诱导的免疫 回应。具体地说，该项目测试了I类新抗原与通用II类新抗原有关的假设 通过临床上可用的CD27的能力，表位将具有良好的耐受性并具有更强的免疫原性 消耗Tregs并同时增强疫苗诱导的患者免疫反应的激动剂抗体 使用GBM。目的1将评估一种新抗原和巨细胞病毒的安全性和治疗潜力 抗原疫苗联合剂量递增的αCD27治疗基底膜。累积结果将 为GBM患者接种新抗原疫苗的可行性和免疫原性提供关键数据 确定是否需要进行更大规模的试验。目标2将确定αCD27是否同时耗尽Treg和Treg 增加疫苗诱导的免疫反应。预计αCD27将减少该患者的Treg 同时改善疫苗诱导的CD8+和CD4+T细胞反应。如果成功，这项工作将 制定针对GBM患者的治疗策略，通过解决以下问题来提高疗效 宿主免疫抑制和瘤内异质性。

ABSTRACT – Project 1 In brain tumors like glioblastoma (GBM), failures to develop an effective vaccine and achieve immune checkpoint inhibition have been attributed to both the remarkable immunosuppression and extraordinary antigenic intratumoral heterogeneity. A major contributor to immunosuppression in GBM is elevated regulatory T-cells (TRegs) which dramatically suppress T cell effector function and diminish the efficacy of antitumor vaccination. Efforts to deplete TRegs by targeting the interleukin-2 receptor α (CD25) have been unsuccessful to date, due to cytotoxic effects on effector T cells, which are required to promote antitumor immunity. To overcome this hurdle, Project 1 builds novel preliminary data demonstrating the ability of a clinically available CD27 agonist antibody (αCD27) to simultaneously deplete TRegs and enhance vaccine-induced immune responses. Specifically, the Project tests the hypothesis that class I neoantigens linked to universal class II epitopes will be well-tolerated and rendered more immunogenic by the ability of the clinically available CD27 agonist antibody to deplete TRegs and simultaneously enhance vaccine-induced immune responses in patients with GBM. Aim 1 will evaluate the safety and therapeutic potential of a neoantigen and Cytomegalovirus antigen vaccine in combination with dose-escalating αCD27 in patients with GBM. Cumulative results will provide critical data on the feasibility and immunogenicity of neoantigen vaccination in patients with GBM to determine if a larger trial is warranted. Aim 2 will determine if αCD27 simultaneously depletes TRegs and increases vaccine-induced immune responses. It is expected that αCD27 will reduce TRegs in this patient population while improving vaccine-induced CD8+ and CD4+ T cell responses. If successful, this work will develop a therapeutic strategy for patients with GBM that has enhanced efficacy by addressing the issues of host immunosuppression and intratumoral heterogeneity.