Antitumor Activity of a Selectively Replication Competent Herpes Simplex Virus (HSV) with Enzyme Prodrug Therapy

Abstract

Background: HSV1790 is an oncolytic virus generated by inserting the enzyme nitroreductase (NTR) into the virus HSV1716. NTR converts the prodrug CB1954 into an active alkylating agent. Materials and Methods: In vitro, 3T6 cells (non permissive to HSV) were used in order to distinguish between virus-induced cytopathic effect and cell death due to activated prodrug. In vivo, xenograft models were injected with HSV1790 (10⁵-10⁹ PFU) with or without CB1954 (max 80mg/kg) and tumor volume recorded regularly. Biodistribution of HSV1790 was determined immunohistochemically and by PCR. Results: HSV1790 + CB1954 in vitro was more effective at killing tumor cells than the virus or the prodrug alone. In vivo, the combination reduced tumor volume and increased survival compared to treatment with HSV1790 or CB1954 alone. Following systemic administration of HSV1790, viral replication was detected in tumors, but not organs. Conclusion: HSV1790 + prodrug enhances tumor cell killing in vitro and reduces tumor volume and increases survival in vivo.