GENE-THERAPY FOR METASTATIC MALIGNANT-MELANOMA - EVALUATION OF TOLERANCE TO INTRATUMORAL INJECTION OF CELLS PRODUCING RECOMBINANT RETROVIRUSES CARRYING THE HERPES-SIMPLEX VIRUS TYPE-1 THYMIDINE KINASE GENE, TOBE FOLLOWED BY GANCICLOVIR ADMINISTRATION

This protocol presents a new therapeutic approach to the treatment of patients with otherwise incurable malignant metastatic melanoma. Its o bjective is to define the safety of escalating doses of an anti-cancer treatment involving intratumoral injections of cells that produce rec ombinant retroviruses. The experimental treatment is based on the intr oduction into tumoral cells of a suicide gene coding for the herpes si mple virus type 1 thymidine kinase (HSV1-TK). Cells that express HSV1- TK become sensitive to ganciclovir (GCV). GCV has no toxicity for norm al cells, but kills cells expressing the HSV1-TK enzyme. Such toxicity is restricted to cells undergoing division. Introduction of the gene into tumoral cells is obtained through the intratumoral injection of m urine fibroblasts modified by genetic engineering (M11 cells). These c ells continuously produce recombinant defective retroviruses containin g the HSV1-TK gene. Retroviruses can integrate their genes only when t he cells they infect are undergoing division. Thus, after intratumoral injection of M11 cells, the tumoral cells, but not the quiescent cell s of the healthy tissue surrounding them, express the HSV1-TK gene and can be destroyed by GCV. In addition, tumoral cells that do not expre ss the gene, but which are located in the immediate vicinity of the tr ansduced cells, are also destroyed through a ''bystander effect,'' als o restricted to cells undergoing division. It is therefore not necessa ry for all the tumoral cells to express HSV1-TK for all of them to be destroyed. Finally, preliminary data suggest that this localized tumor icidal activity may trigger a more general antineoplastic action, by f acilitating a specific antitumoral immune response. The efficacy of th e above therapeutic approach has been evidenced with animals in the tr eatment of brain tumors, of colic adenocarcinoma hepatic metastases an d of malignant melanoma. A therapeutic trial on recurrent brain tumors or metastases has begun in the USA, using a similar approach. We prop ose a phase I-II clinical study of the treatment of metastatic maligna nt melanoma. The patients enrolled in the study must present a metasta tic malignant melanoma that is no longer treatable by conventional the rapy (life expectancy of patients <12 months). Progressively increased doses of M11 tells (1 x 10(8), 2 x 10(8), 3 x 10(8) cells/cm(3) of tu mor) will be injected transcutaneously in the cutaneous, sub-cutaneous or ganglionary tumoral nodules. For a given dosage, four patients rec eiving the treatment will be studied. Four additional patients will be enrolled at the higher tolerated dosage, We will study the safety and the tumoricidal effect of the direct intratumoral injection of M11 ce lls followed by treatment with GCV at a constant, intravenous dosage o f 10 mg/kg/d x 14 days.