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肿瘤微环境（TME）是对有效癌症的主要损害 免疫疗法。免疫能力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 检查点分子CD155。 PVSripo在恶性细胞中表现出潜在的细胞毒性特性，主要是由于 未考虑到病毒蛋白合成的巨大优势的未考虑到PKC-RAF-ERK1/2-MNK信号。 有趣的是，APC的感染具有截然不同的结果。在巨噬细胞或树突状细胞中，PVSripo 感染导致慢性非致病性病毒传播，从而产生1型的持久诱导 干扰素主导刺激。 PVSRIPO感染的APC暴露了增强的抗原抗性和T细胞共介 刺激能力。病毒肿瘤细胞裂解，以及在A中发生的促炎APC刺激 免疫细胞侵入肿瘤的环境，为抗肿瘤免疫史的启动奠定了基础。 PVSripo在一项针对反复发行的1阶段临床试验中表现出了希望 恶性神经胶质瘤（胶质母细胞瘤，胶质肉瘤），并于5月被授予突破性疗法名称， 2016年。在此试验过程中，我们观察到对替莫唑胺或lomustine的有趣反应。 PVSRIPO后肿瘤复发的经历过活检或成像的证据。我们是 追求以下目的：1）单独或在 IV级恶性神经胶质瘤的复发性患者中与Lomustine结合。我们提出了一个 单机构，两臂随机2阶段研究，研究了复发性GBM患者的存活率 单独使用PVSripo和PVSripo + Lomustine化学疗法治疗。研究目标是：a）评估 单剂量的PVSRIPO有或没有单剂量的Lomustine的疗效 GBM相对于在（FDA批准）历史对照组中观察到的生存； b）评估安全性 Lomustine PVSRIPO处理； c）定义因肿瘤内成像而可视化的变化 单独或与Lomustine结合接种PVSripo。 2）进行免疫监测到 机械上解开PVSRIPO免疫疗法与Lomustine协同作用。我们将使用Immunocell 分析和T细胞受体（TCR）测序以评估：a）全球（全血）T细胞群体； b） 效应抗Polio记忆T细胞种群； c）响应自体树突细胞（DC）刺激的T细胞 具有定义的GBM抗原（EGFR，HER2，Survivin，Htert）。