Circumventing Barriers to Effective Oncolytic Virotherapy of Malignant Gliomas

描述（由申请人提供）：恶性胶质瘤（胶质母细胞瘤）的治疗仍然是一个挑战。几种实验范例继续用于临床试验，如溶瘤病毒（OV），在肿瘤中选择性复制的工程或天然存在的病毒株。溶瘤单纯疱疹病毒1型（oHSV）的临床试验已经揭示了其在人类恶性胶质瘤中的安全性，但需要更多的工作来提高其疗效。因此，该项目的研究者假设，在病毒感染和复制的最初阶段，胶质母细胞瘤中的oHSV复制和扩散受到多种基于oHSV和基于宿主的屏障和应答的限制（目的1）。了解自然 这些屏障和应答的研究将使我们能够利用药理学和遗传学方式来规避基于oHSV和基于宿主的屏障和应答，并增加恶性胶质瘤病毒治疗的功效（目的2）。为了实现这些目标，项目1（PI：J. Glorioso）计划重新设计oHSV以将其重定向至神经胶质瘤细胞表面受体，同时使用基于microRNA的oHSV基因的翻译控制来增加其安全性;项目2（PI：E.A. Chiocca）将表征肿瘤细胞内的抗病毒作用的新机制，其基于组蛋白脱乙酰酶之一HDAC 6、其如何与干扰素相互作用以及其如何将进入后oHSV穿梭至溶酶体以进行异源吞噬而不是细胞核以进行主动复制;项目3（PI：B. Kaur）将确定肿瘤微环境的基质如何阻碍oHSV扩散，并将利用软骨素酶来抵消这一点;项目4（PI：M.A. Caligiuri）将显示NK细胞对病毒感染的神经系统肿瘤的快速活化如何对治疗有害，并将表征这种细胞和分子效应物。 反应这5个项目将由核心A提供的独特资源提供服务（生物统计学/管理：Chiocca/Fernadez），为所有项目提供生物统计学依据，核心B（oHSV生产：Goins），为所有项目提供相同的纯化oHSV和核心C库存（胶质瘤生物储存库：中野），其为所有项目提供了患者来源的胶质瘤球状体（GS），其概括了人类肿瘤表型/遗传特征。

DESCRIPTION (provided by applicant): The treatment for malignant glioma (glioblastoma) remains a challenge. Several experimental paradigms continue to be utilized in clinical trials, such as oncolytic viruses (OV), engineered or naturally occurring virus strains that replicate selectively in tumors. Oncolytic herpes simplex virus type 1 (oHSV) clinical trials have revealed its safety in humans with malignant gliomas, but more work is required to increase its efficacy. The investigators of this program project thus hypothesize that oHSV replication and dispersal in glioblastoma is curtailed by multiple oHSV-based and host-based barriers and responses during the very initial phases of viral infection and replication {aim 1). Understanding the nature of these barriers and responses would allow us to exploit both pharmacologic and genetic modalities to circumvent oHSV-based and host-based barriers and responses and increase the efficacy of malignant glioma virotherapy (aim 2). To achieve these aims, project 1 (PI: J. Glorioso) plans to re-engineer oHSV to redirect it towards glioma cell surface receptors while increasing its safety using microRNA-based translational controls of oHSV genes; Project 2 (PI: E.A. Chiocca) will characterize a novel mechanism of antiviral action within tumor cells that is based on one of the histone deacetylases, HDAC6, how it interacts with Interferon and how it shuttles post-entry oHSV towards lysosomes for xenophagy rather than nucleus for active replication; Project 3 (PI: B. Kaur) will determine how the stroma of the tumor microenvironment impedes oHSV dispersal and will utilize chondroitinase to counteract this; Project 4 (PI: M.A. Caligiuri) will show how the rapid NK cell activation against virally infected nervous system tumors is deleterious to therapy and will characterize the cellular and molecular effectors of this response. These 5 projects will be served by the unique resources provided by Core A (Biostatistics/ Administration: Chiocca/Fernadez) that provides biostatistical justification for al projects, Core B (oHSV Production: Goins) that provides all projects with the same stock of purified oHSV and Core C (Glioma Biorepository: Nakano) that provides all projects with patient-derived glioma spheroids (GSs) that recapitulate the human tumor phenotypic/genetic features.