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：
8196839
负责人：
SHAUN XIAOLIU ZHANG
金额：
$ 30.19万
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/8196839
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.

抽象的溶瘤病毒在临床前测试中已被证明安全有效，目前正在对患者进行临床试验患有多种恶性疾病。当前一代的溶瘤单纯疱疹病毒（HSV）是完全由 1 型病毒 (HSV-1) 构建，其肿瘤选择性很大程度上是通过靶向实现的正在分裂的细胞。我们最近从 HSV-2 构建了一种新型溶瘤病毒，可以选择性地在通过激活的 Ras 信号通路裂解肿瘤细胞。命名为FusOn-H2，突变病毒特征多种抗肿瘤机制，包括诱导细胞膜融合（合胞体形成）和肿瘤细胞凋亡，因此在不同肿瘤模型中测试时具有有效的抗肿瘤活性。尽管如此，我们很清楚 FusOn-H2- 成功临床应用的剩余障碍介导的病毒疗法。例如，任何溶瘤病毒的抗肿瘤作用都会因以下因素而大大减弱：宿主的先天免疫在病毒感染期间可以立即激活，因此我们认为干扰先天免疫系统的关键组成部分可能会增强 FusOn- 的溶瘤作用 H2。我们还假设 FusOn-H2 独特的溶瘤机制可用于与化疗联合治疗可进一步增强肿瘤细胞的破坏作用间充质干细胞将作为理想的细胞载体，选择性地、重复地传递溶瘤细胞即使存在主动抗病毒免疫，病毒也会传播到肿瘤组织。我们提出了三个具体目标在体外和体内测试这些预测，长期目标是开发有效且安全的病毒疗法在不久的将来可以转化为临床上有用的策略。的成功成果这些临床前研究将对这部小说未来临床试验的设计产生重大影响溶瘤病毒，因为可以实施一种或多种这些增强策略来增强这种能力病毒疗法。