Development of an HSV-2 based oncolytic virus

描述（由申请人提供）：溶瘤病毒在临床前试验中已被证明是安全有效的，目前正在对各种恶性疾病患者进行临床试验。目前这一代的溶瘤单纯疱疹病毒（HSV）完全由1型病毒（HSV-1）构建，其肿瘤选择性主要通过靶向分裂细胞来实现。我们最近从HSV-2构建了一种新型溶瘤病毒，该病毒可以选择性地在具有激活的Ras信号通路的肿瘤细胞中复制并裂解肿瘤细胞。命名为FusOn-H2的突变病毒具有多种抗肿瘤机制，包括诱导肿瘤细胞中的细胞膜融合（合胞体形成）和凋亡，因此在不同肿瘤模型中测试时具有强效抗肿瘤活性。尽管如此，我们很清楚FusOn-H2介导的病毒疗法的成功临床应用的剩余障碍。例如，任何溶瘤病毒的抗肿瘤作用都被宿主的先天免疫大大削弱，先天免疫可以在病毒感染期间立即激活，这使我们认为干扰先天免疫系统的关键组分可能会增强FusOn-H2的溶瘤作用。我们还假设，FusOn-H2独特的溶瘤机制可以在与化疗的组合方案中被利用，以进一步加强肿瘤细胞的破坏，并且间充质干细胞将作为理想的细胞载体来选择性地和重复地将溶瘤病毒递送到肿瘤组织，即使在存在主动抗病毒免疫的情况下。我们提出了三个具体的目标，在体外和体内测试这些预测，长期目标是开发一种有效和安全的病毒疗法，在不久的将来可以转化为临床上有用的策略。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：在实验室和早期临床试验中，使用病毒杀死肿瘤细胞已经显示出相当大的前景。然而，在这种策略作为一种安全有效的癌症治疗形式获得认可之前，必须克服几个障碍。申请人已经从单纯疱疹病毒2型构建了一种病毒，称为FusOn-H2，其在动物肿瘤模型中产生了令人鼓舞的抗肿瘤活性。他现在建议开发和测试不同的策略来改善FusOn-H2病毒疗法，长期目标是将这种治疗转化为恶性肿瘤患者的临床可行选择。

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.