Proj. 1 Targeting Tumor-Specific Neoepitopes for Glioblastoma Immunotherapy

Catherine J. Wu，MD和大卫A.马里兰州里尔登 项目1：胶质母细胞瘤的个性化新抗原疫苗接种和抗PD-1治疗 总结 胶质母细胞瘤（GBM）是最常见的恶性原发性脑癌， 保持缓和。这些肿瘤对单药免疫治疗反应不佳 由于几个因素，包括GBM是一种免疫冷肿瘤， 缺乏效应T细胞浸润肿瘤微环境。我们已经开发出一种 基于稳健分析的个性化肿瘤新抗原靶向疫苗策略（NeoVax） 测序管道，并已证明了显着的CD 4+和CD 8 + T细胞反应， 在高危黑色素瘤患者中接种新表位肽（Ott & Hu，Nature，2017） 以及新诊断的GBM（Reskin等人，Nature 2019）。此外，在与 研究人员从项目3，我们证明，NeoVax诱导了显着的流入， 肿瘤内免疫效应细胞，包括对免疫调节剂具有特异性的CD 4 + T细胞。 新表位进入GBM肿瘤微环境。我们现在通过进行一个 第二项试验中，NeoVax将与抗PD-1治疗GBM患者相结合， 我们观察到抗PD-1治疗扩大了我们的抗肿瘤免疫应答， 接受NeoVax治疗的黑色素瘤患者。我们设计了我们的试验来解决关键问题 PD-1阻断相对于NeoVax新抗原引发的时机是否影响T细胞记忆 根据Sharpe博士（项目2）最近的工作，PD-1信号传导 关键调节长期T细胞记忆。我们假设抗PD-1治疗可以改善 接受NeoVax治疗的GBM患者的结局和PD-1阻滞的时间 相对于用NeoVax引发的肿瘤新抗原， 多功能长期记忆T细胞反应。我们将评估这些假设， 工作分为三个具体目标。在目标1中，我们将评估PD-1的给药 在新诊断GBM的1b期试验中，在NeoVax预充之前或之后进行阻断 接受标准放疗的患者。我们将评估其实力、广度和 相对于PD-1阻断时间的循环新抗原特异性T细胞应答状态 包括在目标2中接受本试验治疗的患者中的长期T细胞记忆应答。我们将 类似地，询问肿瘤浸润免疫细胞的组成和功能状态， 以及在目标3中的NeoVax加抗PD-1治疗后。目的2和3的T细胞免疫应答将 在核心1中进行分析，而核心2将进行计算和统计分析， 这些数据。

Catherine J. Wu, MD and David A. Reardon, MD Project 1: Personalized Neoantigen Vaccination and Anti-PD-1 Therapy for Glioblastoma Summary Current therapies for glioblastoma (GBM), the most common malignant primary brain cancer, remain palliative. These tumors have responded poorly to single agent immunotherapy approaches due to several factors including the fact that GBM is an immunologically cold tumor with a paucity of effector T cells infiltrating the tumor microenvironment. We have developed a personalized tumor neoantigen-targeting vaccine strategy (NeoVax) based on robust analytic sequencing pipelines and have demonstrated marked CD4+ and CD8+ T cell responses to vaccinated neoepitope peptides among patients with high-risk melanoma (Ott & Hu, Nature, 2017) and with newly diagnosed GBM (Reskin et al., Nature 2019). Furthermore, in collaboration with investigators from Project 3, we demonstrated that NeoVax induced a marked influx of intratumoral immune effector cells, including CD4+ T cells with specificity to an immunizing neoepitope into the GBM tumor microenvironment. We now extend this work by conducting a second trial in which NeoVax will be combined with anti-PD-1 therapy for GBM patients based on our observation that anti-PD-1 therapy broadened anti-tumor immune responses among our melanoma patients treated with NeoVax. We have designed our trial to address the key question whether timing of PD-1 blockade relative to neoantigen priming with NeoVax affects T cell memory responses, based on recent work by Dr. Sharpe (Project 2) demonstrating that PD-1 signaling critically regulates long-term T cell memory. We hypothesize anti-PD-1 therapy will improve outcome for GBM patients undergoing NeoVax therapy and that timing of PD-1 blockade relative to tumor neoantigen priming with NeoVax will critically influence the generation of polyfunctional, long-term memory T cell responses. We will evaluate these hypotheses in work organized into three specific aims. In Aim 1, we will evaluate the administration of PD-1 blockade either before or after NeoVax priming in a phase 1b trial for newly diagnosed GBM patients who are treated with standard radiotherapy. We will evaluate the strength, breadth and state of circulating neoantigen-specific T cell responses relative to timing of PD-1 blockade including long-term T cell memory responses among patients treated on this trial in Aim 2. We will similarly interrogate the composition and functional states of tumor infiltrating immune cells before and after NeoVax plus anti-PD-1 therapy in Aim 3. T cell immune responses for Aims 2 and 3 will be analyzed in Core 1, while Core 2 will perform the computational and statistical analyses of these data.