Antitumor effects of interleukin-12 (IL-12): applications for the immunotherapy and gene therapy of cancer.

Interleukin-12 (IL-12) is a pleiotropic cytokine, formerly termed cytotoxic lymphocyte maturation factor (CLMF) or natural killer cell stimulatory factor (NKSF), which is produced primarily by stimulated macrophages. IL-12 is a disulfide-linked heterodimeric cytokine composed of a 35-kDa light chain (p35) and a 40-kDa heavy chain (p40). Unlike most other cytokines, simultaneous transfection of mammalian cells with two different genes is necessary for the production of biologically active IL-12. IL-12 exerts a variety of biological effects on human T and natural killer (NK) cells in vitro, in addition to its ability to promote cytolytic activity, including direct stimulation of the production of IFN-gamma and other cytokines from peripheral blood T and NK cells. The recent finding that IL-12 directs the development of a TH1 type immune response from naive T cells demonstrates the critical role of IL-12 in regulating the immune response. The characteristics of IL-12 function described above strongly suggest its potential usefulness in cancer therapy. Indeed, our studies demonstrate that IL-12 exerts potent antitumor effects following systemic or local administration. We have shown that IL-12 delivered by retroviral vectors allows high-level expression and effective eradication of established tumor in multiple murine tumor models including MCA207 sarcoma. Successful therapy is associated with acquisition of a state of long-term, specific and protective immunity to subsequent challenge with tumor. We have recently received approval from the Recombinant DNA Advisory Committee to proceed with IL-12 gene therapy in humans.