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

项目3：溶瘤脊髓灰质炎病毒（PVSRIPO）联合CCNU（洛莫司汀）治疗复发性胶质母细胞瘤二期试验

• 批准号: 10477340
• 负责人: DARELL D BIGNER
• 金额: $ 55.08万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10477340
• 关键词: Adult; Antigen Presentation; Antigen-Presenting Cells; Antigens; Attenuated; Autologous Dendritic Cells; Biological Assay; Biopsy; Blood; Brain Neoplasms; Brunhilde Virus; Cells; Chronic; Clinical; Clinical Protocols; Clinical Research; Clinical Trials; Control Groups; Convection; Cytolysis; Cytotoxic T-Lymphocytes; Dendritic Cells; Dose; ERBB2 gene; Ectopic Expression; Epidermal Growth Factor Receptor; Exhibits; Glioblastoma; Grant; Human poliovirus; Image; Immune; Immune response; Immunocompetent; Immunologic Monitoring; Immunosuppression; Immunotherapy; In complete remission; Infection; Infiltration; Inflammatory; Infusion procedures; Institution; Interferons; Internal Ribosome Entry Site; Investigational Therapies; Lomustine; MAPK3 gene; Malignant Glioma; Memory; Microglia; Modeling; Monitor; Myeloid Cells; Neurons; Nitrosourea Compounds; Oncolytic poliovirus; Oral Poliovirus Vaccine; Outcome; Patients; Phase; Phase I Clinical Trials; Phase II/III Trial; Poliomyelitis; Population; Primates; Progressive Disease; Property; Protein Biosynthesis; Protocols documentation; Randomized; Randomized Clinical Trials; Recombinants; Recurrence; Resistance; Rhinovirus; Ribosomes; Rodent; Safety; Signal Transduction; Stimulus; Survival Rate; T cell receptor repertoire sequencing; T memory cell; T-Lymphocyte; Time; Toxicology; Tropism; Tumor Antigens; Tumor Immunity; Tumor Tissue; Viral; Viral Proteins; Whole Blood; arm; cancer cell; cancer immunotherapy; chemotherapy; cytotoxic; effector T cell; experience; genomic RNA; gliosarcoma; human subject; immune checkpoint; macrophage; monocyte; neoplastic cell; neurovirulence; phase 2 study; poliovirus receptor; pre-clinical; radiological imaging; receptor; recruit; response; survivin; synergism; temozolomide; tumor; tumor microenvironment; tumor-immune system interactions; viral genomics

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).

项目摘要 – 项目 3 臭名昭著的免疫抑制性肿瘤微环境（TME）是有效癌症治疗的主要危害 免疫疗法。免疫活性啮齿动物肿瘤模型的临床前证据表明，重组的、非 致病性脊髓灰质炎病毒（PVSRIPO）可以引发肿瘤抗原特异性抗肿瘤免疫，部分是通过 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、免疫细胞 检查点分子CD155。 PVSRIPO 在恶性细胞中表现出有效的细胞毒性特性，这主要是由于 精神错乱的 PKC-Raf-ERK1/2-MNK 信号为病毒蛋白合成提供了巨大的优势。 有趣的是，APC 的感染会产生截然不同的结果。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，从而产生 1 型的持久诱导 以干扰素为主的刺激。 PVSRIPO 感染的 APC 表现出增强的抗原呈递和 T 细胞协同作用 刺激能力。病毒肿瘤细胞裂解，与促炎性 APC 刺激相结合 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 在一项正在进行的针对复发性 WHO IV 期的 1 期临床试验中展现了前景 恶性胶质瘤（胶质母细胞瘤、胶质肉瘤），并于 5 月获得突破性疗法认定， 2016。在这项试验过程中，我们观察到患者对替莫唑胺或洛莫司汀的有趣反应： PVSRIPO 后经历了活检证明或影像学提示的肿瘤复发证据。我们是 追求以下目标： 1) 单独或联合进行 PVSRIPO 的 2 期随机临床试验 与洛莫司汀联合治疗复发性 WHO IV 级恶性胶质瘤患者。我们提出一个 单机构、双臂随机 2 期研究，检查复发性 GBM 患者的生存情况 单独使用PVSRIPO和PVSRIPO+洛莫司汀化疗治疗。研究目标是： a) 评估 单剂量 PVSRIPO 联合或不联合单剂量洛莫司汀对复发性成人患者的疗效 GBM 相对于（FDA 批准的）历史对照组中观察到的生存率； b) 评估安全性 用洛莫司汀治疗PVSRIPO； c) 定义由于瘤内肿瘤而在成像上可视化的变化 单独接种PVSRIPO或与洛莫司汀联合接种。 2) 进行免疫监测 从机制上揭示 PVSRIPO 免疫疗法与洛莫司汀的协同作用。我们将使用免疫细胞 分析和 T 细胞受体 (TCR) 测序以评估： a) 全局（全血）T 细胞群； b) 效应抗脊髓灰质炎记忆T细胞群； c) T 细胞对自体树突状细胞 (DC) 刺激作出反应 具有明确的 GBM 抗原（EGFR、HER2、生存素、hTERT）。