Efficacy of repeated adenoviral suicide gene therapy in a localized murine tumor model

Background. Gene therapy using adenovirus to deliver herpes simplex virus thymidine kinase (Ad.HSV tk) followed by the administration of the prodrug ganciclovir has been an effective anticancer therapy in models of localized tumor (including malignant mesothelioma) and is currently being evaluated in clinical trials. To optimize this approach, we studied the effects of repeated injections of Ad.HSV tk in an animal model of localized tumor in both naive and immunized mice. Methods. Immunocompetent animals with established abdominal tumor were treated with either one or three (given weekly) intraperitoneal injections of Ad.HSV tk (10 9 plaque-forming units) followed by daily ganciclovir and monitored for survival. Survival studies were also performed in mice previously immunized with adenovirus. Results. Animals treated with multiple courses of Ad.HSV tk showed significantly improved survival versus singly injected animals and control animals with some long-term survivors in the multiple injected group. Preexisting neutralizing immunity did not diminish this survival advantage. Conclusions. Multiple treatments using an adenoviral vector to deliver HSV tk significantly improves survival in a murine intraperitoneal tumor model. The presence of preexisting neutralizing antibodies does not blunt this effect. Repeat Ad.HSV tk is a feasible approach and may be a useful strategy in human cancer gene therapy.