APPLICATION OF INTERLEUKIN-12 TO ANTITUMOR CYTOKINE AND GENE-THERAPY

In vivo administration of interleukin 12 (IL-12) at 2000 U/mouse induc ed IL-12-activated killer (IL-12AK) cells in parallel with an elevatio n in serum interferon-gamma (IFN-gamma) activity. Although NK1.1(+)CD3 (-) natural killer cells are the major precursor of IL-12AK cells, asi aloGM1(+)CD8(+) T-cells were also demonstrated to be novel precursors. Such anomalous killer cells may play an important role in the early s tages of the host defense mechanisms against tumors. It was also shown that IL-12 is effective in inducing tumor-specific cytotoxic T-lympho cytes. Consistent with these data, IL-12 had marked activity against v arious kinds of established tumors when given systemically. Mice cured of tumors by IL-12 treatment acquired tumor-specific T-cell immunity. Moreover, we initially demonstrated that IL-12 was effective in preve nting and inhibiting the growth of primary tumors induced by the chemi cal carcinogen methylnitrosourea using c-Ha-ras transgeneic mice. Fina lly, we investigated the application of IL-12 to antitumor gene therap y. Transfer of the IL-12 gene into A20 B-lymphoma cells resulted in th e continuous production of IL-12 and caused abrogation of in vivo tumo rigenicity. Tumor cells transfected with the IL-12 gene are potentiall y a good tool as a tumor vaccine, as they effectively induced IL-12AK cells, IFN-gamma production, and tumor-specific protective immunity. A lthough B16-BL-6 melanoma cells, which are a highly metastatic subclon e of B16 melanoma cells, showed resistance to IL-12 gene therapy, comb ination therapy with the B7-1 gene and systemic IL-12 administration a lmost completely inhibited tumor metastasis. Similar results were obta ined using B16-BL-6 melanoma cells transfected with both B7-1 and IL-1 2 genes. These results suggest that IL-12 is a promising cytokine for antitumor cytokine and gene therapy.