Proj. 1 Targeting Tumor-Specific Neoepitopes for Glioblastoma Immunotherapy

医学博士Catherine J.Wu和医学博士David A.Reardon 项目1：胶质母细胞瘤的个体化新抗原接种和抗PD-1治疗 摘要 胶质母细胞瘤(GBM)是最常见的恶性原发脑癌，目前的治疗方法 保持姑息状态。这些肿瘤对单剂免疫治疗的反应很差。 由于几个因素导致的入路，包括基底膜是一种免疫冷肿瘤的事实 肿瘤微环境中缺乏效应性T细胞。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，并已显示出显著的CD4+和CD8+T细胞对 高危黑色素瘤患者接种新表位多肽(Ott&Hu，自然，2017) 以及新诊断的GBM(Reskin等人，《自然》，2019年)。此外，在与 来自项目3的研究人员，我们证明了NeoVax诱导了显著的 瘤内免疫效应细胞，包括免疫特异性的CD4+T细胞 新表位进入GBM肿瘤微环境。我们现在通过进行一项 NeoVax将联合抗PD-1治疗GBM患者的第二个试验，基于 我们观察到，抗PD-1治疗扩大了抗肿瘤免疫反应。 黑色素瘤患者接受NeoVax治疗。我们设计我们的试验是为了解决关键问题 相对于NeoVax启动新抗原，阻断PD-1的时机是否影响T细胞记忆 基于夏普博士(项目2)最近的工作证明PD-1信号转导 关键地调节长期的T细胞记忆。我们假设抗PD-1治疗将有所改善 接受NeoVax治疗的GBM患者的结局和PD-1阻断的时机 相对于肿瘤新抗原，用NeoVax预充将严重影响 多功能、长期记忆性T细胞反应。我们将在以下文件中评估这些假设 工作组织成三个具体目标。在目标1中，我们将评估PD-1的管理 在新诊断的GBM的1b期试验中，在NeoVax启动之前或之后进行阻断 接受标准放射治疗的患者。我们将评估力量、广度和 循环中新抗原特异性T细胞反应状态与PD-1阻断时间的关系 包括在Aim 2的这项试验中治疗的患者的长期T细胞记忆反应。我们将 类似地，以前询问肿瘤浸润性免疫细胞的组成和功能状态 在AIM 3的NeoVax加抗PD-1治疗后，AIMS 2和3的T细胞免疫反应将 将在核心1进行分析，而核心2将执行以下计算和统计分析 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.