Project 3: Phase-2 Trial of Oncolytic Poliovirus (PVSRIPO) combined with CCNU (lomustine) against Recurrent Glioblastoma

项目概要-项目3 众所周知的免疫抑制肿瘤微环境（TME）是有效癌症的主要损害因素。 免疫疗法免疫活性啮齿动物肿瘤模型中的临床前证据表明，重组、非- 致病性脊髓灰质炎病毒（PVSRIPO）可以引起肿瘤抗原特异性抗肿瘤免疫，部分通过 逆转免疫抑制并产生免疫接合的TME。PVSRIPO靶向肿瘤细胞， 抗原呈递细胞（APC;巨噬细胞/小胶质细胞，树突状细胞）通过其受体，免疫 检查点分子CD 155。PVSRIP 0在恶性细胞中表现出强的细胞毒性，这主要是由于 非铰链的PKC-Raf-ERK 1/2-MNK信号为病毒蛋白合成提供了巨大的优势。 有趣的是，APC的感染具有非常不同的结果。在巨噬细胞或树突状细胞中，PVSRIPO 感染导致慢性、非致细胞病变的病毒繁殖，产生持久的1型诱导 干扰素显性刺激。PVSRIPO感染的APC表现出增强的抗原呈递和T细胞共表达。 刺激能力。病毒肿瘤细胞溶解，结合促炎性APC刺激发生在一个肿瘤细胞中。 在免疫细胞猖獗侵入肿瘤的背景下，为抗肿瘤免疫的启动奠定了基础。 PVSRIPO已在一项针对复发性WHO IV期的正在进行的I期临床试验中显示出前景 恶性胶质瘤（胶质母细胞瘤，胶质肉瘤），并在5月获得突破性治疗指定， 2016.在本试验过程中，我们观察到替莫唑胺或洛莫司汀在以下患者中的有趣反应： PVSRIPO后出现活检证实或影像学提示的肿瘤复发证据。我们 追求以下目标：1）进行PVSRIPO单独或联合 与洛莫司汀联合治疗复发性WHO IV级恶性胶质瘤患者。我们提出了一个 一项检查复发性GBM患者生存率的单机构、双臂、随机、II期研究 用单独的PVSRIPO和PVSRIPO +洛莫司汀化疗治疗。研究目的是：a）评估 单剂量PVSRIPO联合或不联合单剂量洛莫司汀治疗成人复发性 GBM相对于（FDA批准的）历史对照组中观察到的生存率; B）评估 用洛莫司汀进行PVSRIPO治疗;以及c）定义由于肿瘤内注射而在成像上可视化的变化。 接种单独的PVSRIP 0或与洛莫司汀组合。2)进行免疫监测， 在某些实施方案中，本发明的方法可以在机械上阐明PVSRIP 0与洛莫司汀的免疫治疗协同作用。我们将使用免疫细胞 分析和T细胞受体（TCR）测序以评估：a）总体（全血）T细胞群; B） 效应抗脊髓灰质炎记忆T细胞群; c）响应自体树突细胞（DC）刺激的T细胞 具有确定的GBM抗原（EGFR、HER 2、存活素、hTERT）。

PROJECT SUMMARY – Project 3 The notoriously immunosuppressive tumor microenvironment (TME) is a major detriment to effective cancer immunotherapy. Pre-clinical evidence in immunocompetent rodent tumor models show that recombinant, non- pathogenic poliovirus (PVSRIPO) can elicit tumor antigen-specific antitumor immunity, in part through reversing immunosuppression and generating an immune-engaged TME. PVSRIPO targets tumor cells and antigen presenting cells (APCs; macrophages/microglia, dendritic cells) via its receptor, the immune checkpoint molecule CD155. PVSRIPO exhibits potent cytotoxic properties in malignant cells, largely due to unhinged PKC-Raf-ERK1/2-MNK signals that provide an enormous advantage to viral protein synthesis. Intriguingly, infection of APCs has a very different outcome. In macrophages or dendritic cells, PVSRIPO infection leads to chronic, non-cytopathogenic viral propagation that produces durable induction of type 1 interferon-dominant stimulation. PVSRIPO-infected APCs exhibit enhanced antigen-presentation and T cell co- stimulation capacity. Viral tumor cell lysis, combined with pro-inflammatory APC stimulation occurring in a context of rampant immune cell invasion into the tumor, set the stage for initiation of antitumor immunity. PVSRIPO has demonstrated promise in an ongoing Phase 1 clinical trial against recurrent WHO stage IV malignant glioma (glioblastoma, gliosarcoma) and was granted Breakthrough Therapy Designation in May, 2016. In the course of this trial, we observed intriguing responses to temozolomide or lomustine in patients that experienced biopsy-proven or imaging-suggested evidence for tumor recurrence post PVSRIPO. We are pursuing the following Aims: 1) Conduct a Phase 2 randomized clinical trial of PVSRIPO alone or in combination with lomustine in patients with recurrent WHO Grade IV malignant glioma. We propose a single-institution, two-arm randomized Phase 2 study that examines the survival of recurrent GBM patients treated with PVSRIPO alone and PVSRIPO + lomustine chemotherapy. Study objectives are: a) to assess the efficacy of a single dose of PVSRIPO with or without a single dose of lomustine among adults with recurrent GBM relative to the survival observed in a (FDA sanctioned) historical control group; b) to assess the safety of PVSRIPO treatment with lomustine; and c) to define changes visualized on imaging due to intratumoral inoculation of PVSRIPO alone or in combination with lomustine. 2) Perform immune monitoring to mechanistically unravel PVSRIPO immunotherapy synergy with lomustine. We will use immune cell profiling and T Cell Receptor (TCR) sequencing to assess: a) global (whole blood) T cell populations; b) effector anti-polio memory T cell populations; c) T cells responding to autologous dendritic cell (DC) stimulus with defined GBM antigens (EGFR, HER2, survivin, hTERT).