Circumventing barriers to effective oncolytic virotherapy of malignant gliomas

项目总结--总体 我们建议对溶瘤性单纯疱疹病毒(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。这类生物制剂(最近由 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，随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。这第一阶段导致直接的肿瘤细胞毒性，产生炎症反应和 释放肿瘤抗原，激活第二阶段的细胞毒性T细胞反应，导致持久的 病毒疗法的抗癌活性。 在当前的周期中，我们发现OHSV的初始阶段受到快速和早熟的阻碍。 天然免疫系统的细胞，即自然杀伤细胞和巨噬细胞清除OHSV。我们的 总体假设是NK细胞和巨噬细胞被召入基底膜微环境以 在足够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在免疫的临床成功的基础上加以扩展 检查点(IC)阻断是OHSV介导的免疫刺激和GBM炎症的必然结果 当与恢复T细胞激活(通过免疫检查点阻断)相结合时，会导致持久的 “抗基底膜”效应。 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 针对肿瘤细胞表面病毒抗原的激活(项目4-DR)。俄亥俄州立大学 综合癌症中心)和/或抑制激活OHSV感染的肿瘤细胞信号 NK细胞(项目1--DR)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，UTHealth)，和(B)增加免疫检查点抑制 OHSV治疗(项目2--Dr。乔卡，布里格姆和妇女医院/达纳·法伯癌症研究所， BWH/DFCI)。 此外，该PPG将使用OHSV对复发的GBM患者进行“首例人”临床试验。 其开发工作是在本供资期间完成的。项目2将提供临床 将样本转移到其他项目和核心，以便对实验结果进行临床验证。三 核心提供OHSV制剂(核心1-Dr.Goins，UPMC)、小鼠和人类GBM细胞(核心2-DR)。利贡， DFCI)和生物统计分析(CORE 3-DR)。费尔南德斯，OSUCCC)。我们的团队由病毒学专家组成， 癌症生物学、免疫学和具有生物疗法的临床试验，在评估 OHSV治疗复发性基底膜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.