ANTITUMOR EFFECTS OF THE COMBINATION IMMUNOTHERAPY WITH INTERLEUKIN-12 AND TUMOR-NECROSIS-FACTOR-ALPHA IN MICE

There is strong evidence that antitumor activity of interleukin-12 (IL -12) in vivo is mediated, in part, through interferon (IFN gamma) prod uced by IL-12-stimulated natural killer and T cells. Since IFN gamma a nd tumor necrosis factor alpha (TNF alpha) have been reported to syner gize in antitumor effects in a number of models, we decided to examine whether the combined treatment with recombinant mouse IL-12 and recom binant human TNF alpha would produce similar effects. The efficacy of the combined IL-12/TNF alpha immunotherapy was evaluated in three tumo r models in mice: B16F10 melanoma, Lewis lung (LL/2) carcinoma and L1 sarcoma. Intratumoral daily injections of 1 mu g IL-12 in combination with 5 mu g TNF alpha into B16F10-melanoma-bearing mice resulted in a significant retardation of the tumor growth as compared with that in c ontrols and in mice treated with either cytokine alone. Similar effect s were obtained using 0.1 mu g IL-12 and 5 mu g TNF alpha in LL/2 carc inoma and L1 sarcoma models. Antitumor activity against L1 sarcoma was still preserved when TNF alpha at a low dose (1 mu g) was combined wi th 0.1 mu g IL-12 and applied for a prolonged time. Potentiation of an titumor effects, which was observed in IL-12/TNF alpha-based immunothe rapy, could result from at least three different mechanisms, partly re lated to stimulation of IFN gamma and TNF alpha production in treated mice: (a) direct cytostatic/cytotoxic effects on tumor cells, (b) indu ction of antitumor activity of macrophages, and (c) inhibition of bloo d vessel formation in the tumor. Our studies demonstrate that combinat ion tumor immunotherapy with IL-12 and TNF alpha may be more effective than single-cytokine treatment, and suggest possible mechanisms by wh ich IL-12 and TNF alpha may exert potentiated therapeutic effects agai nst locally growing tumors.