title: Experimental gene therapy of cancer using tumor cells engineered to secrete interleukin-13.
abstract: Cytokines locally delivered to the site of a tumor boost both specific and nonspecific host anti-tumor defenses. Interleukin (IL)-13 is a recently described cytokine produced by mouse type 2 helper T lymphocytes. The aim of this study was to evaluate the inhibition of tumor growth induced by IL-13 delivered locally within or around transplanted tumor cells in mice. We observed that local administration of IL-13 at the site of transplanted tumor cells in vivo had potent inhibitory effects on growth of both immunogenic (P815 mastocytoma, H-2d) or nonimmunogenic (3LL lung carcinoma, H-2b) tumor cells. Mice injected with transfected P815 cells secreting large amounts of IL-13 rejected the P815 tumor and developed systemic specific anti-tumor immunity leading to long-lasting specific anti-tumor protection. Less efficient anti-tumoral effects were obtained with the nonimmunogenic 3LL tumor model when local administration of IL-13 was achieved by co-inoculating xenogeneic chinese hamster ovary (CHO) IL-13 cells. Several local injections of CHO IL-13 cells were needed to obtain rejection of 3LL tumors and no induction of long-lasting anti-3LL memory was obtained. Several studies were performed to elucidate the IL-13 anti-tumoral effects. Experiments with nude mice indicated that Il-13 can also stimulate nonspecific anti-tumor defenses. The histological examination of P815 IL-13 cells undergoing rejection showed monocytic cells and neutrophils infiltrating the tumor. Studies indicated that IL-13 administered in vitro did not directly stimulate the cytotoxicity of peritoneal macrophages and natural killer cells. However, experiments with Boyden chemotaxis chambers indicated that IL-13 was chemotactic for macrophages. Finally, preliminary experiments in vitro suggest that IL-13 improved antigenic presentation of P815 membranes. Thus, anti-tumor effects of IL-13 in vivo most probably result from pleiotropic effects including recruitment of nonspecific cells and improved stimulation of immune-specific anti-tumor effectors.
authors.affiliation: Laboratoire Immunomodulation et Autoimmunité, INSERM U283, Hôpital Cochin, Paris, France.
authors.forename: S
authors.initials: S
authors.lastname: Lebel-Binay
authors.forename: B
authors.initials: B
authors.lastname: Laguerre
authors.forename: F
authors.initials: F
authors.lastname: Quintin-Colonna
authors.forename: H
authors.initials: H
authors.lastname: Conjeaud
authors.forename: M
authors.initials: M
authors.lastname: Magazin
authors.forename: B
authors.initials: B
authors.lastname: Miloux
authors.forename: F
authors.initials: F
authors.lastname: Pecceu
authors.forename: D
authors.initials: D
authors.lastname: Caput
authors.forename: P
authors.initials: P
authors.lastname: Ferrara
authors.forename: D
authors.initials: D
authors.lastname: Fradelizi
mesh_terms: D000818:Animals; D002634:Chemotaxis, Leukocyte; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D018793:Interleukin-13 / Q000096:biosynthesis / Q000235:genetics* / Q000627:therapeutic use; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000276:immunology / Q000628:therapy*; D014162:Transfection / Q000502:physiology*; D014407:Tumor Cells, Cultured
chemical_list: D018793:Interleukin-13