CURE OF MICE WITH ESTABLISHED METASTATIC FRIEND-LEUKEMIA CELL TUMORS BY A COMBINED THERAPY WITH TUMOR-CELLS EXPRESSING BOTH INTERFERON-ALPHA-1 AND HERPES-SIMPLEX THYMIDINE KINASE FOLLOWED BY GANCICLOVIR

Transduction of the murine interferon-alpha (IFN-alpha) gene into vari ous malignant mouse tumor cells has resulted in the loss of tumorigeni city and an acquired capacity to induce long-lasting antitumor immunit y following their injection into immunocompetent syngeneic mice. In th e present study, we investigated the effectiveness of IFN-alpha-produc ing tumor cells in the therapy of mice with established mouse tumors. In DBA/2 mice bearing subcutaneous (s.c.) Friend erythroleukemia cell (FLC) tumors, we found that to achieve some antitumor response (i) it was necessary to inject high numbers of IFN-alpha-producing FLC, which occasionally lead to the formation of slowly growing tumors; and, tha t (ii) repeated injections of irradiated IFN-alpha-FLC did not result in any antitumor effect. The therapeutic potential of IFN-alpha-produc ing FLC rendered sensitive to ganciclovir (GCV), by transfer of the he rpes simplex virus thymidine kinase (tk) gene, was investigated Comple te tumor rejection and cure was observed in greater than or equal to 7 0% of the animals after injection of high numbers (10(7)) of IFN-alpha -producing tk-expressing tumor cells followed 4 days later by repeated GCV treatments, whereas only a slight increase in survival time was o btained after administration of control fk-expressing tumor cells (not producing IFN) and GCV. Tumor rejection was associated with a dramati c destruction of tumor tissue and with the subsequent development of a potent and long-lasting antitumor immunity. No therapeutic effect was observed in immunosuppressed nude mice. These data indicate that this approach may represent an effective and safe therapeutic strategy for antitumor cytokine gene therapy.