Experimental gene therapy of cancer using tumor cells engineered to secrete interleukin-13.
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.
Lebel-Binay
S
S
Laboratoire Immunomodulation et Autoimmunité, INSERM U283, Hôpital Cochin, Paris, France.
Laguerre
B
B
Quintin-Colonna
F
F
Conjeaud
H
H
Magazin
M
M
Miloux
B
B
Pecceu
F
F
Caput
D
D
Ferrara
P
P
Fradelizi
D
D
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
D018793:Interleukin-13