Development of an HSV-2 based oncolytic virus

基于 HSV-2 的溶瘤病毒的开发

• 批准号: 7925372
• 负责人: SHAUN XIAOLIU ZHANG
• 金额: $ 11.33万
• 依托单位: UNIVERSITY OF HOUSTON
• 依托单位国家: 美国
• 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/7925372
• 关键词: Acute; Animals; Antineoplastic Agents; Antiviral Agents; Apoptosis; Apoptotic; Autologous; Binding; Cell Cycle; Cell membrane; Cells; Cessation of life; Clinical; Clinical Trials; Cytolysis; Data; Development; Disease; Future; Gene Delivery; Generations; Genes; Giant Cells; Goals; Herpesvirus 1; Home environment; Human Herpesvirus 2; Immune; Immune system; Immunity; In Vitro; Laboratories; Malignant - descriptor; Mediating; Membrane Fusion; Mesenchymal Stem Cells; Modeling; Natural Immunity; Oncolytic; Oncolytic viruses; Outcome; Pathway interactions; Patients; Phase; Play; Preclinical Testing; Property; Proteins; Radiation; Radiation therapy; Ras Signaling Pathway; Resistance; Role; Route; SLC5A5 gene; STAT1 gene; Simplexvirus; Small Interfering RNA; Testing; Therapeutic; Tissues; Transcript; Translating; Treatment Protocols; Tumor Tissue; Viral Genome; Virus; Virus Diseases; Virus Replication; base; cancer therapy; cell killing; chemotherapy; clinical application; design; gene therapy; improved; in vivo; killings; macrophage; monocyte; mutant; neoplastic cell; novel; preclinical study; public health relevance; ras GTPase-Activating Proteins; success; synergism; tumor

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Using viruses to kill tumor cells has shown considerable promise in the laboratory and in early clinical trials. Yet several obstacles must be overcome before this strategy gains acceptance as a safe and potent form of cancer therapy. The applicant has constructed a virus from herpes simplex virus type 2, called FusOn-H2, which has produced encouraging antitumor activity in animal tumor models. He now proposes to develop and test different strategies for improving FusOn-H2 virotherapy, with the long-term goal of translating this treatment into a clinically feasible option for patients with malignant sold tumors.

描述（由申请人提供）：溶瘤病毒已被证明在临床前测试中是安全有效的，现在正在针对各种恶性疾病的患者进行临床试验。当前的溶瘤疱疹病毒（HSV）仅由1型病毒（HSV-1）构建，其肿瘤选择性在很大程度上通过靶向分裂细胞来实现。最近，我们从HSV-2构建了一种新型的溶瘤病毒，可以在用激活的RAS信号通路中选择性地复制并裂解肿瘤细胞。指定的Fuson-H2，突变病毒具有多种抗肿瘤机制，包括诱导细胞膜融合（合成曲霉形成）和肿瘤细胞中凋亡，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，我们非常了解成功临床应用fuson-H2介导的病毒疗法的障碍。例如，宿主的先天免疫力大大降低了任何溶瘤病毒的抗肿瘤作用，这种免疫力可以在病毒感染过程中立即激活，这使我们暗示干扰对先天免疫系统的关键成分可能会增强fuson-H2的癌化作用。我们还假设，可以用化学疗法的组合方案来利用熔融H2的独特溶肿机制，以进一步增强肿瘤细胞破坏，并且间充质干细胞将作为理想的细胞载体作为理想的细胞载体，以选择性地并反复将肿瘤病毒传递到肿瘤组织中，即使在有活跃的抗病毒抗体中，也可以将其运送到肿瘤组织中。我们提出了三个特定的目的，旨在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的病毒疗法，该疗法可以在不久的将来转化为临床上有用的策略。这些临床前研究的成功结果将对这种新型溶瘤病毒的未来临床试验的设计具有重要意义，因为可以实施这些增强策略中的一种或多种来增强这种病毒疗法。公共卫生相关性：使用病毒杀死肿瘤细胞已在实验室和早期临床试验中表现出巨大的希望。然而，在这种策略接受作为一种安全且有效的癌症治疗形式之前，必须克服几个障碍。申请人已经从单纯疱疹病毒2型（称为Fuson-H2）中构建了一种病毒，该病毒在动物肿瘤模型中产生了鼓励的抗肿瘤活性。现在，他建议制定和测试改善Fuson-H2病毒疗法的不同策略，其长期目标是将这种治疗方法转化为恶性销售肿瘤患者的临床可行选择。