ANTITUMOR AND ANTIMETASTATIC ACTIVITY OF INTERLEUKIN-12 AGAINST MURINE TUMORS

It has recently been demonstrated that in vivo administration of murin e interleukin 12 (IL-12) to mice results in augmentation of cytotoxic natural killer (NK)/lymphocyte-activated killer cell activity, enhance ment of cytolytic T cell generation, and induction of interferon gamma secretion. In this study, the in vivo activity of murine IL-12 agains t a number of murine tumors has been evaluated. Experimental pulmonary metastases or subcutaneous growth of the B16F10 melanoma were markedl y reduced in mice treated intraperitoneally with IL-12, resulting in a n increase in survival time. The therapeutic effectiveness of IL-12 wa s dose dependent and treatment of subcutaneous tumors could be initiat ed up to 14 d after injection of tumor cells. Likewise, established ex perimental hepatic metastases and established subcutaneous M5076 retic ulum cell sarcoma and Renca renal cell adenocarcinoma tumors were effe ctively treated by IL-12 at doses which resulted in no gross toxicity. Local peritumoral injection of IL-12 into established subcutaneous Re nca tumors resulted in regression and complete disappearance of these tumors. IL-12 was as effective in NK cell-deficient beige mice or in m ice depleted of NK cell activity by treatment with antiasialo GM1, sug gesting that NK cells are not the primary cell type mediating the anti tumor effects of this cytokine. However, the efficacy of IL-12 was gre atly reduced in nude mice suggesting the involvement of T cells. Furth ermore, depletion of CD8+ but not CD4+ T cells significantly reduced t he efficacy of IL-12. These results demonstrate that IL-12 has potent in vivo antitumor and antimetastatic effects against murine tumors and demonstrate as well the critical role of CD8+ T cells in mediating th e antitumor effects against subcutaneous tumors.