Circumventing Barriers to Effective Oncolytic Virotherapy of Malignant Gliomas

描述(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。几种实验范式继续被用于临床试验，例如溶瘤病毒(OV)，即在肿瘤中选择性复制的工程或自然发生的病毒株。溶瘤单纯疱疹病毒1型(OHSV)临床试验表明，它对患有恶性胶质瘤的人类是安全的，但需要更多的工作来提高其疗效。因此，该项目的研究人员假设，在病毒感染和复制的最初阶段，OHSV在胶质母细胞瘤中的复制和扩散受到基于OHSV和基于宿主的多种屏障和反应的抑制。了解这些障碍和反应的性质将使我们能够利用药物和遗传方式来绕过基于HSV和基于宿主的障碍和反应，并增加恶性胶质瘤病毒治疗的疗效(目标2)。为了实现这些目标，项目1(PI：J.Glorioso)计划重新设计OHSV，将其重新定向到胶质瘤细胞表面受体，同时利用OHSV基因的基于microRNA的翻译控制来提高其安全性；项目2(PI：E.A.Chiocca)将描述一种新的肿瘤细胞内抗病毒作用的机制，该机制基于组蛋白去乙酰基酶HDAC6，它如何与干扰素相互作用，以及进入OHSV后如何将OHSV运送到溶酶体用于异源吞噬，而不是用于主动复制的核；项目3(PI：B.Kaur)将确定肿瘤微环境的基质如何阻碍OHSV的扩散，并将利用软骨素酶来抵消这一作用；项目4(PI：M.A.Caligiuri)将展示针对病毒感染的神经系统肿瘤的快速NK细胞激活如何对治疗有害，并将描述这种反应的细胞和分子效应。这5个项目将由核心A(生物统计/管理：Chiocca/Fernadez)提供的独特资源提供服务，核心A(生物统计/管理：Chiocca/Fernadez)为AL项目提供生物统计理由，核心B(OHSV生产：GOINS)为所有项目提供相同库存的纯化OHSV，以及核心C(胶质瘤生物库：Nakano)提供所有项目患者来源的胶质瘤球体(GSS)，概括人类肿瘤的表型/基因特征。

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.