Development of an HSV-2 based oncolytic virus

基于 HSV-2 的溶瘤病毒的开发

基本信息

批准号：
8528758
负责人：
SHAUN XIAOLIU ZHANG
金额：
$ 2.28万
依托单位：
UNIVERSITY OF HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-12-01 至 2013-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8528758
关键词：
Acute Animal Model Animals Antineoplastic Agents Antiviral Agents Apoptosis Binding CXCL12 gene Cell Cycle Cell membrane Cells Characteristics Chemicals Clinical Clinical Trials Clinical Trials Design Cytolysis Data Decitabine Development Development Plans Dichloroacetate Disease Energy Metabolism Engineering Future GTPase-Activating Proteins Gene Delivery Gene Expression Generations Genes Giant Cells Goals Growth Herpesvirus 1 Human Herpesvirus 2 Immune system Immunity In Vitro Induction of Apoptosis Laboratories Malignant - descriptor Malignant Neoplasms Mediating Membrane Fusion Mesenchymal Stem Cells Modeling Natural Immunity Normal Cell Oncolytic Oncolytic viruses Outcome Pathway interactions Patients Pharmaceutical Preparations Phase Play Preclinical Testing Property Proteins Ras Signaling Pathway Regimen Resistance Role Route S Phase Simplexvirus Staging Testing Therapeutic Toxic effect Toxicology Translating Treatment Efficacy Tumor Tissue Viral Virus Virus Diseases Virus Replication Work abstracting base cancer therapy cell killing chemotherapy clinical application design gemcitabine gene therapy improved in vivo killings mutant neoplastic cell novel preclinical study ras GTPase-Activating Proteins success trafficking tumor

项目摘要

Abstract Oncolytic viruses have proved safe and effective in preclinical testing and are now in clinical trials for patients with a variety of malignant diseases. The current generation of oncolytic herpes simplex viruses (HSVs) was constructed exclusively from type 1 virus (HSV-1) and their tumor selectivity was largely achieved by targeting dividing cells. We recently constructed a novel oncolytic virus from HSV-2 that can selectively replicate in and lyse tumor cells with an activated Ras signaling pathway. Designated FusOn-H2, the mutant virus features multiple antitumor mechanisms, including the induction of cell membrane fusion (syncytia formation) and apoptosis in tumor cells, and thus has potent antitumor activity when tested in different tumor models. Nonetheless, we are well aware of the remaining barriers to successful clinical application of FusOn-H2- mediated virotherapy. For example, the antitumor effect of any oncolytic virus is greatly diminished by the host's innate immunity, which can be instantly activated during virus infection, leading us to suggest that interference with key components of the innate immune system might enhance the oncolytic effects of FusOn- H2. We also hypothesize that the unique oncolytic mechanisms of FusOn- H2 could be exploited in combination regimens with chemotherapy to further potentiate the tumor cell destruction, and that mesenchymal stem cells would function as ideal cell carriers to selectively and repeatedly deliver the oncolytic virus to tumor tissues, even in the presence of active antiviral immunity. We have proposed three specific aims to test these predictions both in vitro and in vivo, with the long-term goal of developing a potent and safe virotherapy that could be translated into a clinically useful strategy in the near future. Successful outcomes of these preclinical studies will have significant implications for the design of future clinical trials of this novel oncolytic virus, as one or more of these enhancement strategies may be implemented to potentiate this virotherapy.

抽象的溶瘤病毒已被证明是安全有效的，在临床前测试中有效，现在正在针对患者进行临床试验患有多种恶性疾病。当前一代的溶瘤疱疹单纯疱疹病毒（HSV）是仅从1型病毒（HSV-1）构建，其肿瘤选择性在很大程度上通过靶向实现分裂细胞。我们最近从HSV-2构建了一种新型的溶瘤病毒，可以选择性地复制和用激活的RAS信号通路裂解肿瘤细胞。指定的Fuson-H2，突变病毒特征多种抗肿瘤机制，包括诱导细胞膜融合（合成形成）和在不同肿瘤模型中测试时，肿瘤细胞中的凋亡，因此具有有效的抗肿瘤活性。尽管如此，我们很清楚成功地临床应用Fuson-H2-- 介导的病毒疗法。例如，任何肿瘤病毒的抗肿瘤作用都大大减少了宿主的先天免疫力可以在病毒感染期间立即激活，这使我们暗示干扰先天免疫系统的关键组成部分可能会增强熔融效应 H2。我们还假设，可以在结合方案与化学疗法，以进一步增强肿瘤细胞的破坏，并间充质干细胞将充当理想的细胞载体，以选择性并反复传递溶瘤即使在有活性抗病毒药性的情况下，病毒至肿瘤组织。我们提出了三个具体目标在体外和体内测试这些预测，其长期目标是开发有效且安全在不久的将来，可以将病毒疗法转化为临床上有用的策略。成功的结果这些临床前研究将对这部新小说的未来临床试验的设计具有重要意义溶瘤病毒，可能会实施这些增强策略中的一种或多种，以增强这种增强病毒疗法。