Efficacy and safety of a third-generation oncolytic herpes virus G47Δ in models of human esophageal carcinoma

Treatment options are limited for esophageal carcinoma (EC). G47 Delta, a triple-mutated, conditionally replicating herpes simplex virus type 1 (HSV-1), exhibits enhanced killing of tumor cells with high safety features. Here, we studied the efficacy of G47 Delta using preclinical models of human EC. In vitro, G47 Delta showed efficient cytopathic effects and replication capabilities in all eight human esophageal cancer cell lines tested. In athymic mice harboring subcutaneous tumors of human EC (KYSE180, TE8, and OE19), two intratumoral injections with G47 Delta significantly inhibited the tumor growth. To mimic the clinical treatment situations, we established an orthotopic EC model using luciferase-expressing TE8 cells (TE8-luc). An intratumoral injection with G47 Delta markedly inhibited the growth of orthotopic TE8-luc tumors in athymic mice. Furthermore, we evaluated the safety of applying G47 Delta to the esophagus in mice. AUJ mice inoculated intraesophageally or administered orally with G47 Delta (10(7) plaque-forming units [pfu]) survived for more than 2 months without remarkable symptoms, whereas the majority with wild-type HSV-1 (10(6) pfu) deteriorated within 10 days. PCR analyses showed that the G47 Delta DNA was confined to the esophagus after intraesophageal inoculation and was not detected in major organs after oral administration. Our results provide a rationale for the clinical use of G47 Delta for treating EC.