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

项目摘要--项目3 众所周知的免疫抑制肿瘤微环境(TME)是有效治疗癌症的主要障碍。 免疫疗法。免疫活性啮齿动物肿瘤模型的临床前证据表明，重组、非 致病性脊髓灰质炎病毒(PVSRIPO)可诱导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参与的TME。PVSRIPO靶向肿瘤细胞和 抗原提呈细胞(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CD155。PVSRIPO在恶性细胞中表现出强大的细胞毒特性，这主要是由于 脱节的PKC-Raf-ERK1/2-MNK信号为病毒蛋白质合成提供了巨大的优势。 有趣的是，感染APC的结果却截然不同。在巨噬细胞或树突状细胞中，PVSRIPO 感染导致慢性、非细胞病理性病毒传播，从而产生持久的1型诱导 干扰素为主的刺激。PVSRIPO感染的APC表现出抗原提呈增强和T细胞协同 刺激能力。病毒肿瘤细胞溶解，结合促炎APC刺激发生在 在免疫细胞侵袭肿瘤的背景下，为启动抗肿瘤免疫奠定了基础。 PVSRIPO在正在进行的针对WHO IV期复发的1期临床试验中展示了希望 恶性胶质瘤(胶质母细胞瘤、胶质肉瘤)，并于5月份获得突破性治疗称号， 2016年。在该试验过程中，我们观察到患者对替莫唑胺或洛莫司汀的耐人寻味的反应。 有经验的活检-证实或成像-建议的证据表明，PVSRIPO术后肿瘤复发。我们是 追求以下目标：1)进行PVSRIPO单独或联合治疗的2期随机临床试验 联合洛莫司汀治疗复发的WHO IV级恶性胶质瘤我们提出了一个 一项单机构、双臂随机第二阶段研究，检查复发GBM患者的存活率 单用PVSRIPO和PVSRIPO+洛莫司汀化疗。研究目标是：a)评估 单剂PVSRIPO联合或不联合单剂洛莫司汀治疗成人复发的疗效观察 GBM相对于(FDA批准的)历史对照组中观察到的生存期；b)评估 使用洛莫司汀的PVSRIPO治疗；以及c)定义由于肿瘤内而在成像上可见的变化 单独接种PVSRIPO或与洛莫司汀联合接种。2)进行免疫监测， 机械地解开PVSRIPO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)全球(全血)T细胞种群；b) 效应器抗脊髓灰质炎记忆T细胞群；c)对自体树突状细胞(DC)刺激反应的T细胞 具有已定义的GBM抗原(EGFR、HER2、Survivin、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).