PRODUCTION OF INTERLEUKIN-2 BY EL4 TUMOR-CELLS INDUCES NATURAL-KILLERCELL-MEDIATED AND T-CELL-MEDIATED IMMUNITY

Systemic administration of recombinant interleukin (rIL)-2 to cancer p atients has met with limited clinical success since, despite significa nt antitumor effects, its use is associated with severe toxicity. Loca l production of IL-2 by IL-2 gene transfected tumor cells in murine mo del systems has been reported to induce specific immunity-devoid of to xicity-to the parental non-IL-2-producing tumor cells. We now report e nhanced resistance in nonimmunized mice to murine EL4 thymoma cells, p roducing murine IL-2 following gene transfer (EL4pIL-2). This effect i s mediated by activated natural killer (NK) cells, since we observed t he same effect in nude mice but not in NK-depleted mice. Additionally, in mice repeatedly vaccinated with irradiated EL4pIL-2 cells, we obse rved immunity to challenge with a tumorigenic dose of EL4 cells transf ected with a control vector, EL4p. EL4-specific cytotoxic T-lymphocyte s (CTLs) were detected in these mice. Mice vaccinated with irradiated EL4p cells were less protected against challenge with a tumorigenic do se of EL4p cells. This study indicates that although some IL-2-produci ng autologous tumor cells elicit NK-mediated responses and not CTL res ponses upon inoculation, tumor-specific CTL responses are generated up on repeated vaccinations with these cells. This strategy has potential application for treating a wide variety of cancer patients with autol ogous IL-2 producing tumor cells.