We performed a dose-escalating phase I/II study of retrovirus-mediated herpes simplex virus type 1
thymidine kinase (HSV-1-TK) suicide gene therapy for metastatic
melanoma. HSV-1 TK expression, which specifically sensitizes transduced and bystander
cancer cells to
ganciclovir (GCV) toxicity, was mediated by one (four patients, first dose step) to three (four patients, second dose step)
injections of "M11" retrovirus vector-producing cells in
melanoma cutaneous nodules. After a 7-day period allowed for
cancer cell transduction, GCV was administered for 14 days. Safety was assessed by clinical and laboratory evaluations, and efficacy was assessed by
tumor measurements and histology. M11 doses ranged from 76 to 1247 x 10(6) cells. Treatment-related adverse events were mild and transient, limited to inflammatory skin reactions at injection and
fever on repeated
injections. Plasma GCV was in the active range (>0.2 microg/ml); transgene was detected by polymerase chain reaction in three of six patients; treated
tumor size was moderately affected under GCV as compared with untreated
tumors, although 2 weeks after GCV administration important (>50%) treated-
tumor necrosis was evidenced on histology in three of eight patients. All patients showed
disease progression on long-term follow-up. Thus, M11-mediated HSV-1 TK gene therapy was well tolerated over a wide dose range. The limited
tumor response is likely to be related to poor gene transfer efficiency. However,
necrosis following GCV administration in transduced
tumors indicates a potential for treatment efficacy.