LOCAL AND SYSTEMIC ANTITUMOR RESPONSE AFTER COMBINED THERAPY OF MOUSEMETASTATIC TUMORS WITH TUMOR-CELLS EXPRESSING IFN-ALPHA AND HSVTK - PERSPECTIVES FOR THE GENERATION OF CANCER VACCINES

In this study, we have evaluated the local versus systemic antitumor r esponse in tumor-bearing mice subjected to a combined therapeutic regi men based on the injection of genetically modified Friend erythroleuke mia cells (FLC) producing IFN-alpha and expressing the HSVik (tk) gene , and we have investigated the host immune mechanisms involved in tumo r rejection and development of antitumor immunity. Repeated subcutaneo us (s.c.) injections of IFNtk-expressing tumor cells, followed by GCV administration, were effective in counteracting the growth of both con tralateral parental tumors as well as visceral metastases, whereas sim ilar treatments with control tk cells (ie nonproducing IFN) were ineff ective. Morphologic analyses of the homolateral and contralateral tumo r tissues and in vivo immunosuppression experiments with specific mono clonal antibodies revealed that both CD4(+) and CD8(+) T lymphocytes p layed essential roles in the generation of a definite antitumor respon se after the combined therapeutic regimen. We have also compared the e ffectiveness of irradiated versus viable tumor vaccines coexpressing t he two genes in the FLC model and in the poorly immunogenic, metastasi zing TS/A adenocarcinoma tumor system. Repeated injections of high dos es of irradiated IFN-alpha-tk-expressing tumor cells followed by GCV a dministration resulted in the cure of the majority of mice bearing est ablished metastatic tumors, while repeated inoculations of the same nu mber of viable tumor vaccines were much less effective. We conclude th at: (1) IFN-alpha is an essential cofactor in the generation of a syst emic antitumor immunity following the prodrug-induced tumor cell killi ng, (2) vaccines co-expressing an autotoxic gene and a cytokine gene m ay represent promising new tools for the treatment of some cancer pati ents.