Oncolytic herpes simplex viral therapy effectively treats and improves survival in a murine model of pleural malignant mesothelioma

Abstract

Introduction: Replication-competent, attenuated herpes simplex virus type-1 (HSV-1) selectively infect and lyse cancer cells. The purpose of this study was to determine whether HSV-1 therapy was cytotoxic to malignant mesothelioma (MM) cell lines and improves survival in a murine model of MM. Methods: In Vitro: Eleven human MM cell lines were infected with HSV-1 strain, NV1066 at multiplicities of infection (MOI: number of viral particles per cancer cell) of 0.01, 0.1 or 1. Cell kill was determined by LDH (Lactate dehydrogenase release) assay and viral replication by plaque assay. In Vivo: MSTO-211H, MM cells were injected percutaneously into the pleural cavity of the nude mice. Pleural disease and body weight were monitored after treatment with intrapleural injection of either NV1066, 1x107 pfu (plaque forming units) (n = 10) or saline (n = 10). Survival was monitored after early (day 5) or late (day 11) treatment with a single dose of NV1066, 1x107 pfu or saline (n = 20 each group). Results: In Vitro: NV1066 was cytotoxic to all the cell lines (average 89 ± 3% cell kill at MOI of 1, p<0.01) with increase in viral titers to 105–3600 fold. In Vivo: Mice treated with NV1066 retained their body weights (p<0.01). By day 21, only 2/10 treated animals had pleural disease compared to 10/10 control mice. The median survival for the early treated group was 95 v/s 19 days (logrank p value <0.001) and the late treated group was 48 v/s 20 days (p = 0.002). Conclusions: Oncolytic herpes simplex viral therapy was cytotoxic against MM cell lines and improves survival in a murine model.