A Phase I/II Dose-Escalation Study of Herpes Simplex Virus Type 1 Thymidine Kinase “Suicide” Gene Therapy for Metastatic Melanoma

Abstract

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 × 10⁶ 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 μg/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.

Overview summary

Expression of the herpes simplex virus type 1 thymidine kinase gene specifically sensitizes transduced and bystander cancer cell to ganciclovir toxicity. Suicide gene therapy based on HSV-1 TK gene transfer has demonstrated significant tumoricidal effect at nontoxic doses in many preclinical models, including melanoma and brain tumors. We report here the results of a phase I/II clinical trial based on in situ administration of HSV-1 TK retroviral vector-producing cells for malignant melanoma. The treatment was well tolerated over a wide dose range, including repeated injections. Although we observed a poor gene transfer efficiency, important treated-tumor necrosis could be evidenced on histology in three of eight patients. Thus, optimization of the treatment modalities to achieve better gene transfer might improve the overall treatment efficacy.