Circumventing barriers to effective oncolytic virotherapy of malignant gliomas

项目概要-总体 我们提出了溶瘤单纯疱疹病毒（oHSV）的临床前和临床研究，用于治疗 胶质母细胞瘤（GBM），一种致命且不可治愈的肿瘤。这类生物制剂（最近获得批准， FDA的黑色素瘤）被认为是通过两种机制发挥其作用： 感染肿瘤细胞，随后是一系列的病毒子代产生和感染扩散， 邻近的肿瘤细胞。第一阶段导致直接的肿瘤细胞毒性，产生炎症反应， 释放肿瘤抗原，激活细胞毒性T细胞反应的第二阶段，负责持久的免疫应答。 病毒疗法的抗癌活性。 在目前的周期中，我们发现oHSV作用的初始阶段受到快速和过早的抑制。 通过先天免疫系统的细胞清除oHSV，即，自然杀伤（NK）细胞和巨噬细胞。我们 总体假设是NK细胞和巨噬细胞被称为GBM微环境， 在病毒复制和肿瘤细胞毒性充分之前，快速去除oHSV感染的肿瘤细胞 发生。认识到这一假设需要基于免疫治疗的临床成功进行扩展， 检查点（IC）阻断，必然结果是oHSV介导的免疫刺激和GBM炎症 当与T细胞活化的恢复（通过免疫检查点阻断）结合时， “抗GBM”效应。 我们的四个项目提出了两种总体方法来验证这些假设：（a）直接抑制NK细胞受体 针对肿瘤细胞表面上的病毒抗原的活化（项目4-Caligiuri博士; The俄亥俄州州立大学 综合癌症中心，OSUCCC）和/或抑制oHSV感染的肿瘤细胞信号传导，所述肿瘤细胞信号传导激活 NK细胞（项目1-Glorioso博士;匹兹堡大学医学中心，UPMC）和巨噬细胞（项目1-巨噬细胞） 3-Kaur博士，德克萨斯大学健康科学，UTHealth），和（B）添加免疫检查点抑制 oHSV治疗（项目2-Dr. Chiocca，Brigham and Women's Hospital/Dana Farber Cancer Institute， 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。 其开发已在当前供资期间完成。项目2将提供临床 其他项目和核心的样本，以便对实验结果进行临床验证。三 核心提供oHSV制备物（核心1-Dr. Goins，UPMC）、小鼠和人GBM细胞（核心2-Dr. Ligon， DFCI）和生物统计学分析（核心3-费尔南德斯博士，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，并具有独特的地位，以评估 oHSV治疗复发性GBM患者的临床前和临床疗效。

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.