Circumventing barriers to effective oncolytic virotherapy of malignant gliomas

克服恶性胶质瘤有效溶瘤病毒治疗的障碍

• 批准号: 10491137
• 负责人: MICHAEL A CALIGIURI
• 金额: $ 176.64万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-07 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10491137
• 关键词: Biological Products; Biological Response Modifier Therapy; Biometry; Cancer Biology; Cell surface; Cells; Clinical; Clinical Research; Clinical Trials; Comprehensive Cancer Center; Coupled; Cytolysis; Cytotoxic T-Lymphocytes; Dana-Farber Cancer Institute; Development; Elements; Engineering; Ensure; FDA approved; Funding; Genomics; Glioblastoma; Health Sciences; Hospitals; Human; Immune; Immune checkpoint inhibitor; Immune response; Immune system; Immunization; Immunology; Immunotherapy; Infection; Inflammation; Inflammatory Response; Innate Immune System; Knowledge; Malignant Glioma; Malignant Neoplasms; Mediating; Medical center; Metastatic Melanoma; Mus; Mutation; Natural Killer Cells; Neoplasms; Notch Signaling Pathway; Ohio; Oncolytic viruses; Outcome; Patients; Phase; Population; Positioning Attribute; Preparation; Production; Prognosis; Reagent; Receptor Activation; Receptor Cell; Recurrence; Reproducibility; Research; Sampling; Signal Transduction; T cell response; T-Cell Activation; Testing; Texas; Time; Treatment Failure; Tumor Antigens; Tumor Virus Infections; Universities; Validation; Viral; Viral Antigens; Virotherapy; Virus; Virus Diseases; Virus Replication; Woman; anti-CTLA4; anti-PD-1; anti-PD-L1; anticancer activity; base; cancer recurrence; checkpoint inhibition; clinical efficacy; comparative; cytotoxicity; exhaust; experimental study; first-in-human; genetically engineered virus; immune checkpoint blockade; macrophage; melanoma; mouse model; neoplastic cell; oncolytic herpes simplex virus; oncolytic virotherapy; patient derived xenograft model; preclinical efficacy; preclinical study; premature; programs; response; restoration; success; tumor; tumor microenvironment; virology

PROJECT SUMMARY - OVERALL We propose preclinical and clinical studies of oncolytic Herpes simplex viruses (oHSVs) for the therapy of glioblastoma (GBM), a deadly and incurable neoplasm. This class of biologic agents (recently approved by the FDA for melanoma) are thought to exert their effects through two mechanisms: there is an initial phase of OV infection of tumor cells, followed by serial rounds of viral progeny production and spread of the infection to adjacent tumor cells. This first phase results in direct tumor cytotoxicity, produces inflammatory responses and release of tumor antigens that activate a second phase of cytotoxic T cell responses, responsible for the durable anticancer activity of virotherapy. During the current cycle, we discovered that the initial phase of oHSV action is hindered by rapid and premature clearance of oHSVs by cells of the innate immune system, i.e., natural killer (NK) cells and macrophages. Our overall hypothesis is that NK cells and macrophages are called into the GBM microenvironment to rapidly remove oHSV-infected tumor cells, before sufficient viral replication and tumor cytotoxicity occurs. Recognizing that this hypothesis requires broadening based on the clinical success of immune checkpoint (IC) blockade, a corollary is that oHSV-mediated immunostimulation and GBM inflammation when coupled with restoration of T cell activation (via immune checkpoint blockade) leads to a durable “anti-GBM” effect. Our four projects propose two overall approaches to test these hypotheses: (a) direct inhibition of NK cell receptor activation against viral antigens on tumor cell surfaces (Project 4-Dr. Caligiuri; The Ohio State University Comprehensive Cancer Center, OSUCCC) and/or inhibition of oHSV-infected tumor cell signaling that activate NK cells (Project 1-Dr. Glorioso; University of Pittsburgh Medical Center, UPMC) and macrophages (Project 3- Dr. Kaur, University of Texas Health Sciences, UTHealth), and (b) addition of immune checkpoint inhibition to oHSV therapy (Project 2-Dr. Chiocca, Brigham and Women's Hospital/Dana Farber Cancer Institute, BWH/DFCI). Further, this PPG will perform a “first-in-man” clinical trial in recurrent GBM patients using an oHSV whose development was completed during the current funding period. Project 2 will provide the clinical samples to the other Projects and Cores to allow for the clinical validation of experimental outcomes. Three Cores provide oHSV preparation (Core 1- Dr. Goins, UPMC), mouse and human GBM cells (Core 2-Dr. Ligon, DFCI) and biostatistical analyses (Core 3-Dr. Fernandez, OSUCCC). Our group comprises experts in virology, cancer biology, immunology, and clinical trials with biologic therapies and is uniquely positioned to assess the preclinical and clinical efficacy of oHSV therapy for patients with recurrent GBM.

项目概要 - 总体 我们建议对溶瘤单纯疱疹病毒 (oHSV) 进行临床前和临床研究，用于治疗 胶质母细胞瘤（GBM），一种致命且无法治愈的肿瘤。此类生物制剂（最近经国家药监局批准） FDA 治疗黑色素瘤）被认为通过两种机制发挥作用： OV 的初始阶段 肿瘤细胞的感染，然后是一系列病毒后代的产生和感染的传播 邻近的肿瘤细胞。第一阶段导致直接肿瘤细胞毒性，产生炎症反应并 释放肿瘤抗原，激活细胞毒性 T 细胞反应的第二阶段，负责持久的 病毒疗法的抗癌活性。 在当前周期中，我们发现 oHSV 作用的初始阶段受到快速和过早的阻碍 先天免疫系统细胞（即自然杀伤 (NK) 细胞和巨噬细胞）清除 oHSV。我们的 总体假设是 NK 细胞和巨噬细胞被调入 GBM 微环境中 在充分的病毒复制和肿瘤细胞毒性之前快速清除 oHSV 感染的肿瘤细胞 发生。认识到这一假设需要根据免疫疗法的临床成功进行扩大 检查点 (IC) 阻断，推论是 oHSV 介导的免疫刺激和 GBM 炎症 当与 T 细胞激活的恢复（通过免疫检查点封锁）相结合时，会产生持久的 “抗GBM”作用。 我们的四个项目提出了两种总体方法来检验这些假设：(a) 直接抑制 NK 细胞受体 激活肿瘤细胞表面的病毒抗原（项目 4-Dr. Caligiuri；俄亥俄州立大学 综合癌症中心，OSUCCC）和/或抑制 oHSV 感染的肿瘤细胞信号激活 NK 细胞（项目 1-Dr. Glorioso；匹兹堡大学医学中心，UPMC）和巨噬细胞（项目 3- Kaur 博士，德克萨斯大学健康科学大学 (UTHealth)，以及 (b) 添加免疫检查点抑制 oHSV 治疗（项目 2-Chiocca 博士，布莱根妇女医院/达纳法伯癌症研究所， BWH/DFCI）。 此外，该 PPG 将使用 oHSV 在复发性 GBM 患者中进行“首次人体”临床试验 其开发已在当前资助期内完成。项目2将提供临床 样本到其他项目和核心，以便对实验结果进行临床验证。三 核心提供 oHSV 制剂（核心 1-Goins 博士，UPMC）、小鼠和人类 GBM 细胞（核心 2-Ligon 博士、 DFCI）和生物统计分析（核心 3-Fernandez 博士，OSUCCC）。我们的团队由病毒学专家组成， 癌症生物学、免疫学和生物疗法的临床试验，具有独特的地位来评估 oHSV 治疗复发性 GBM 患者的临床前和临床疗效。