B7-1 AND INTERLEUKIN-12 SYNERGISTICALLY INDUCE EFFECTIVE ANTITUMOR IMMUNITY

Enhanced host rejection of tumor cells is the primary goal of cancer i mmunotherapy and, in many murine tumor models, has been accomplished b y engineering cells to express B7 costimulatory molecules or creating an environment rich in certain cytokines. We examined the effect of tu mor cell B7-1 expression and administered recombinant interleukin 12 ( IL-12) on the syngeneic host response to rapidly growing, poorly immun ogenic SCK mammary carcinoma cells and to more slowly growing, immunog enic K1735 melanoma cells. Whereas B7-1 expression induced rejection o f K1735 cells in 78% of mice, and IL-12 induced rejection in 38%, B7-1 expression induced rejection of SCK cells in only 28% of mice, and IL -12 induced rejection in none. The relative ineffectiveness of either B7-1 or IL-12 alone to induce rejection of SCK cells led us to combine the two manipulations. This resulted in rejection of SCK cells in 74% of mice and dramatically delayed tumor development in the remainder. Tumor rechallenge studies indicated that the surviving mice developed specific immunity to wild-type SCK cells. Lymphocyte subset ablation a nd IFN-gamma depletion studies indicated that rejection of SCK tumor c ells brought about by the synergistic effects of B7-1 and IL-12 is med iated by a rapidly developing, systemic antitumor immune response that is dependent on the presence of both CD8(+) and CD4(+) T cells and in volves IFN-gamma. Additionally, the synergistic effect of B7-1 express ion and IL-12 administration is capable of inducing rejection of contr ol SCK tumors simultaneously established in the opposite flank. The ef ficacy of B7-1 and IL-12 in inducing protective immunity against a poo rly immunogenic, aggressive murine tumor indicates that this combinati on is particularly effective at producing a potent antitumor immune re sponse that may be of therapeutic benefit.