TRANSDUCTION OF HUMAN-MELANOMA CELLS WITH INTERLEUKIN-2 GENE REDUCES TUMORIGENICITY AND ENHANCES HOST ANTITUMOR IMMUNITY - A NUDE-MOUSE MODEL

Human melanoma tumor cells were genetically modified in vitro by trans ferring the interleukin-2 (IL-2) gene via a retroviral vector into est ablished or fresh tumor cells. In addition, human melanoma cells were transduced in vivo by the direct injection of the IL-2/retroviral vect or into melanoma xenografts in nude mice. The gene-modified melanoma c ells expressed the IL-2 cytokine gene and secreted biologically active IL-2. Transduction of melanoma cells with the IL-2 gene did not affec t the antigenic profile of the cells, but caused a strong abrogation o f their tumorigenicity. One million parental cells formed subcutaneous tumors in nude mice. In contrast, various doses of up to 20 X 10(6) I L-2-transduced cells failed to form tumor in the mice. Coinjection of 1L-2-producing cells with parental cells inhibited tumor formation eve n when highly tumorigenic doses of parental cells were used. Histochem ical analysis of the injection sites of IL-2-modified cells showed an influx of host immune cells, predominantly macrophages, as early as th e third day after inoculation. Neutrophils, mast cells, and eosinophil s were also seen in the inflammatory exudate. Eventually, transduced c ells showed signs of degeneration and necrosis and ultimately died in 4 weeks. Macrophages were seen in parental tumor sites only during the first few days after injection, and then parental tumors exhibited fa st, progressive growth. The study suggests that melanoma cells transdu ced with the IL-2 cytokine gene may provide an effective vaccine for m elanoma patients, whereas the in vivo transduction of tumors with cyto kine genes is feasible and may represent a novel approach for the immu notherapy of cancer patients. (C) 1994 Academic Press, Inc.