Oncolytic Virus Targets Brain Tumors

描述(申请人提供)：胶质母细胞瘤是侵袭性和侵袭性的脑肿瘤，通常会导致一年内死亡。目前还没有治愈方法，目前的治疗方法只能延长几个月的生命。在目前的应用中，我们建议研究水泡性口炎病毒(VSV)选择性感染和杀死这些脑瘤的潜在用途。我们已经开发出选择性感染人胶质母细胞瘤而不是体外对照细胞的重组VSV，并将其靶向移植到小鼠脑内。由于这些病毒具有复制能力，在杀死第一轮胶质母细胞瘤后，释放出后代病毒，这些病毒以细胞溶解的方式感染更多的胶质母细胞瘤细胞。实验是基于体外使用人和鼠的胶质母细胞瘤和对照细胞，以及将人或鼠的肿瘤细胞移植到小鼠的大脑中。计划进行四组实验。在第一组实验中，重组VSV将被用来测试这样的假设，即增强细胞干扰素反应或减缓复制将选择性地保护正常细胞，但不会保护脑瘤细胞。然后，选择性感染胶质母细胞瘤的VSV将被用于体内实验，其中表达红色报告基因的人胶质母细胞瘤细胞被移植到SCID小鼠的大脑中，或者红色小鼠胶质母细胞瘤被移植到正常免疫能力的小鼠大脑中。VSV将直接注射到脑瘤中，或通过全身注射到尾静脉来测试病毒将选择性地感染和杀死大脑内的胶质母细胞瘤细胞，而不会扩散到正常脑组织的假设。为了提高与脑部溶瘤病毒相关的安全性，第三组体外和体内实验将测试几种已被报道有效控制病毒感染的抗病毒药物(干扰素、利巴韦林、阿司匹林、聚C、IL-12)，以确定哪种药物在阻断正常大脑可能的VSV感染方面最有效。外周VSV免疫将减轻后来由重组VSV引起的脑感染的假设将得到验证。最后一组实验将检验这样的假设，即重组VSV在体外人脑的非肿瘤切片中没有或相对较少的感染和复制。这些研究的主要目的是测试变种溶瘤VSVs作为目前无法治愈的人脑肿瘤潜在治疗的第一步的有效性和安全性。

DESCRIPTION (provided by applicant): Glioblastoma are aggressive and invasive brain tumors that generally lead to death within a year of diagnosis. No cure is available, and current treatments prolong life by only a few months. In the current application, we propose to study the potential use of vesicular stomatitis virus (VSV) to selectively infect and kill these brain tumors. We have developed recombinant VSVs that selectively infect human glioblastoma and not control cells in vitro, and target glioblastoma cells transplanted into the mouse brain. As these viruses are replication-competent, after killing the first round of glioblastoma, progeny viruses are released which cytolytically infect more glioblastoma cells. Experiments are based on in vitro use of human and mouse glioblastoma and control cells, and on human or mouse tumor cells transplanted into the mouse brain. Four sets of experiments are planned. In the first set of experiments, recombinant VSVs will be used to test the hypothesis that enhancing the cellular interferon response or slowing replication will selectively protect normal, but not brain tumor, cells. VSVs that selectively infect glioblastoma will then be used with in vivo experiments in which human glioblastoma cells that express a red reporter gene are transplanted into the brains of SCID mice, or red mouse glioblastoma is transplanted into the normal immunocompetent mouse brain. VSV will be administered either directly into the brain tumor, or by systemic injection into the tail vein to test the hypothesis that the virus will selectively infect and kill the glioblastoma cells within the brain with little spread to the normal brain tissue. To increase the safety profile related to oncolytic viruses in the brain, a third set of in vitro and in vivo experiments will test several antiviral drugs (interferons, ribavirin, aspirin, polylC, IL-12) that have been reported to be effective in controlling viral infections to determine which is the most efficacious in blocking possible VSV infections of normal brain. The hypothesis that peripheral VSV immunization will attenuate a later cerebral infection by recombinant VSV will be tested. A final set of experiments will test the hypothesis that recombinant VSV will show no, or relatively little infection and replication in non-tumor slices of the human brain in vitro. The primary goal of these studies is to test the efficacy and safety of variant oncolytic VSVs as the first step as a potential treatment for currently incurable human brain tumors.