B7-1 and Interleukin 12 Synergistically Induce Effective Antitumor Immunity1

Enhanced host rejection of tumor cells is the primary goal of cancer immunotherapy and, in many murine tumor models, has been accom plished hy engineering cells to express B7 costimulatory molecules or creating an environment rich in certain cytokines. We examined the effect of tumor cell B7-1 expression and administered recombinant interleukin 12 (IL-12) on the syngeneic host response to rapidly growing, poorly immunogenic SCK mammary carcinoma cells and to more slowly grow ing, immunogenic K1735 melanoma cells. Whereas B7-1 expression in duced rejection of K1735 cells in 78% of mice, and 11-12 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 11-12 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 remain der. Tumor rechallenge studies indicated that the surviving mice devel oped specific immunity to wild-type SCK cells. Lymphocyte subset abla tion and II N-y depletion studies indicated that rejection of SCK tumor cells brought about by the synergistic effects of B7-1 and II -12 is mediated by a rapidly developing, systemic antitumor immune response that is dependent on the presence of both CDS* and <'1)4 ' T cells and involves IFN-y. Additionally, the synergistic effect of B7-1 expression and IL-12 administration is capable of inducing rejection of control SCK tumors simultaneously established in the opposite flank. The efficacy of B7-1 and IL-12 in inducing protective immunity against a poorly immunogenic, aggressive murine tumor indicates that this combination is particularly effective at producing a potent antitumor immune response that may be of therapeutic benefit.