Oncolytic viruses have shown considerable promise for the treatment of solid tumors. In previous studies, we demonstrated that a novel oncolytic virus (FusOn-H2), constructed by replacing the serine/threonine protein kinase (PK) domain of the ICP10 gene of type 2 herpes simplex virus (HSV-2) with the gene encoding the green fluorescent protein, can selectively replicate in and thus lyse tumor cells. 4T1 tumor cells are weakly immunogenic and the mammary tumors derived from them aggressively metastasize to different parts of body, thus providing an attractive model for evaluating anticancer agents. We thus tested the antitumor effect of FusOn-H2 in this tumor model, in comparisons with several other oncolytic HSVs derived from HSV-1, including a nonfusogenic HSV-1 (Baco-1) and a doubly fusogenic virus (Synco-2D). Our results show that FusOn-H2 and Synco-2D have greater oncolytic activity in vitro than Baco-1. Moreover, FusOn-H2 induced strong T cell responses against primary and metastatic mammary tumors in vivo, and splenocytes adoptively transferred from FusOn-H2-treated mice effectively prevented metastasis in naïve mice bearing implanted mammary tumors. We conclude that the HSV-2-based FusOn-H2 oncolytic virus may be an effective agent for the treatment of both primary and metastatic breast cancer.

Purpose: We recently constructed an oncolytic virus from type 2 herpes simplex virus that selectively targets and kills tumor cells with an activated Ras signaling pathway. Designated FusOn-H2, this virus has shown several discrete killing mechanisms. Here, we evaluated the antitumor immune responses after FusOn-H2^mediated virotherapy in a syngeneic murine neuroblastoma model. Experimental Design: We directly injected FusOn-H2 into established tumors and then measured its antitumor effect and the accompanying tumor-specific immune responses. Several oncolytic HSVs constructed from HSV-1were included in the same experiments for comparisons. Results: Our data show that tumor destruction by FusOn-H2 in vivo induces potent antitumor immune responses in this syngeneic neuroblastoma model. The elicited cellular immunity not only eradicated neuroblastoma cells in vitro but also inhibited the growth of tumors at sites distant from the virus injection site. Moreover, adoptive transfer of splenocytes from mice receiving virotherapy to naI« ve mice resulted in a measurable antitumor effect. Conclusion: We conclude that the ability of FusOn-H2 to induce tumor-specific cellular immunity expands the oncolytic repertoire of this virus and increases the likelihood that its use in patients would produce significant therapeutic benefits.