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.
Tahara
H
H
Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh Cancer Institute, PA 15261.
Lotze
M T
MT
D016475:3T3 Cells / Q000378:metabolism / Q000637:transplantation; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D017321:Clinical Trials, Phase I as Topic; D004354:Drug Screening Assays, Antitumor; D015316:Genetic Therapy; D006801:Humans; D007155:Immunologic Factors / Q000627:therapeutic use*; D007167:Immunotherapy; D015552:Injections, Intralesional; D018664:Interleukin-12 / Q000235:genetics / Q000502:physiology / Q000627:therapeutic use*; D008252:Macaca fascicularis; D051379:Mice; D008815:Mice, Inbred Strains; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000628:therapy*; D009374:Neoplasms, Experimental / Q000276:immunology / Q000628:therapy; D018123:Receptors, Interleukin / Q000502:physiology; D053707:Receptors, Interleukin-12; D011994:Recombinant Proteins / Q000378:metabolism / Q000627:therapeutic use; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid
D007155:Immunologic Factors; D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; D011994:Recombinant Proteins; D018664:Interleukin-12