Efficacy of repeated adenoviral suicide gene therapy in a localized murinetumor model

Background. Gene therapy using adenovirus to deliver herpes simplex virus t hymidine kinase (Ad.HSVtk) followed by the administration of the prodrug ga nciclovir has been an effective anticancer therapy in models of localized t umor (including malignant mesothelioma) and is currently being evaluated in clinical trials. To optimize this approach, we studied the effects of repe ated injections of Ad.HSVtk in an animal model of localized tumor in both n aive and immunized mice. Methods. Immunocompetent animals with established abdominal tumor were trea ted with either one or three (given weekly) intraperitoneal injections of A d.HSVtk (10(9) plaque-forming units) followed by daily ganciclovir and moni tored for survival. Survival studies were also performed in mice previously immunized with adenovirus. Results. Animals treated with multiple courses of Ad.HSVtk showed significa ntly improved survival versus singly injected animals and control animals w ith some long-term survivors in the multiple injected group. Preexisting ne utralizing immunity did not diminish this survival advantage. Conclusions. Multiple treatments using an adenoviral vector to deliver HSVt k significantly improves survival in a murine intraperitoneal tumor model. The presence of preexisting neutralizing antibodies does not blunt this eff ect. Repeat Ad.HSVtk is a feasible approach and may be a useful strategy in human cancer gene therapy. (Ann Thorac Surg 2000;70:1865-71) (C) 2000 by T he Society of Thoracic Surgeons.