Murine models of cancer cytokine gene therapy using interleukin-12.
Cytokine gene therapy, in particular IL-12 gene therapy, is one of the more novel and promising approaches in cancer therapy based on significant preclinical data derived mainly from murine tumor models. IL-12 is a heterodimeric cytokine that requires the simultaneous expression of both the p35 and p40 chains from the same cell for production of biologically active IL-12. A variety of biological functions have been attributed to IL-12 including the induction of IFN-gamma production and the promotion of predominantly Th1-type immune responses to antigens. Our previous studies using systemic administration of recombinant murine IL-12 have demonstrated profound antitumor efficacy against all tumors tested with the concomitant long-lived specific antitumor immunity in some cases. To determine whether the local secretion of IL-12 achieved by gene transduction has significant antitumor effects, fibroblast cell lines or murine tumor cell lines were transduced with expression plasmids or the retroviral vector TFG-mIL-12-Neo and inoculated intradermally (i.d.). Our first study using IL-12-transfected NIH3T3 cells admixed with the murine melanoma, BL-6, showed that local IL-12 expression suppresses tumor growth and promotes the acquisition of specific antitumor immunity. Subsequent studies showed that IL-12 gene therapy is also effective in treating established day 3 tumors. CD4+ and CD8+ T cells, as well as NK cells, appear to play important roles in the observed antitumor effects resulting from IL-12 paracrine secretion. Administration of neutralizing antibody specific for IFN-gamma also abrogated some of the IL-12-associated antitumor effects. Finally, this IL-12 gene therapy strategy to elicit an antitumor immune response was more effective when used in combination with the transduction of tumor cells with B7.1. Based on these promising results, a clinical protocol for the treating patients with cancer using genetically engineered fibroblasts to express IL-12 has been initiated at our institution.
Tahara
H
H
Department of Surgery, University of Pittsburgh School of Medicine, Pennsylvania, USA.
Zitvogel
L
L
Storkus
W J
WJ
Robbins
P D
PD
Lotze
M T
MT
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D018122:B7-1 Antigen / Q000008:administration & dosage; D015316:Genetic Therapy; D005822:Genetic Vectors; D007111:Immunity, Cellular; D007371:Interferon-gamma / Q000502:physiology; D018664:Interleukin-12 / Q000008:administration & dosage*; D007694:Killer Cells, Natural / Q000276:immunology; D051379:Mice; D009374:Neoplasms, Experimental / Q000628:therapy*; D014161:Transduction, Genetic; D014162:Transfection
D000970:Antineoplastic Agents; D018122:B7-1 Antigen; D018664:Interleukin-12; D007371:Interferon-gamma