Development of an HSV-2 based oncolytic virus

摘要 溶瘤病毒已在临床前试验中被证明是安全有效的，现在正在进行患者的临床试验 患有多种恶性疾病。当代的溶瘤单纯疱疹病毒(HSV)是 仅由1型病毒(HSV-1)构建，其肿瘤选择性在很大程度上是通过靶向实现的 分割细胞。我们最近从HSV-2中构建了一种新的溶瘤病毒，它可以选择性地在 通过激活的RAS信号通路溶解肿瘤细胞。命名为Fuson-H2的突变病毒具有 多种抗肿瘤机制，包括诱导细胞膜融合(合胞体形成)和 在不同的肿瘤模型中测试时，具有很强的抗肿瘤活性。 尽管如此，我们清楚地意识到成功应用Fuson-H2-的仍然存在的障碍- 中介病毒疗法。例如，任何溶瘤病毒的抗肿瘤作用都会因为 宿主的先天免疫，在病毒感染期间可以立即激活，这导致我们认为 干扰先天免疫系统的关键成分可能会增强Fuson的溶瘤作用- H2。我们还假设，Fuson-H2独特的溶瘤机制可以在 联合化疗进一步加强对肿瘤细胞的破坏， 间充质干细胞可以作为理想的细胞载体，选择性和重复地输送溶瘤。 病毒传播到肿瘤组织，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目标 为了在体外和体内检验这些预测，长期目标是开发一种有效和安全的 病毒疗法可能在不久的将来转化为临床有用的策略。取得的成功成果 这些临床前研究将对这一新的未来临床试验的设计具有重要意义 溶瘤病毒，因为可以实施这些增强策略中的一个或多个来增强这一点 病毒疗法。

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.