A PHASE I II DOSE-ESCALATION STUDY OF HERPES-SIMPLEX VIRUS TYPE-1 THYMIDINE KINASE SUICIDE GENE-THERAPY FOR METASTATIC MELANOMA/

We performed a dose-escalating phase I/II study of retrovirus-mediated herpes simplex virus type 1 thymidine kinase (HSV-I-TK) suicide gene therapy for metastatic melanoma. HSV-1 TK expression, which specifical ly sensitizes transduced and bystander cancer cells to ganciclovir (GC V) toxicity, was mediated by one (four patients, first dose step) to t hree (four patients, second dose step) injections of ''M11'' retroviru s 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, a nd efficacy was assessed by tumor measurements and histology. M11 dose s ranged from 76 to 1247 x 10(6) cells. Treatment-related adverse even ts were mild and transient, limited to inflammatory skin reactions at injection and fever on repeated injections. Plasma GCV was in the acti ve range (>0.2 mu g/ml); transgene was detected by polymerase chain re action in three of six patients; treated tumor size was moderately aff ected under GCV as compared with untreated tumors, although 2 weeks af ter GCV administration important (>50%) treated-tumor necrosis was evi denced on histology in three of eight patients. All patients showed di sease progression on long-term follow-up. Thus, Mil-mediated HSV-I TK gene therapy was well tolerated over a wide dose range. The limited tu mor response is likely to be related to poor gene transfer efficiency. However, necrosis following GCV administration in transduced tumors i ndicates a potential for treatment efficacy.