IL-12 IS AN EFFECTIVE ADJUVANT TO RECOMBINANT VACCINIA VIRUS-BASED TUMOR VACCINES - ENHANCEMENT BY SIMULTANEOUS B7-1 EXPRESSION

A number of cytokines and costimulatory molecules involved in immune a ctivation have recently been identified including IL-12, a heterodimer ic cytokine that supports the development of cell-mediated immunity, a nd B7-1, a costimulatory molecule involved in the activation of T lymp hocytes, We explored the use of these immunomodulants as molecularly d efined adjuvants in the function of recombinant anticancer vaccines us ing a murine model adenocarcinoma, CT26, transduced with a model Ag, b eta-galactosidase (beta-gal), Although IL-12 given alone to mice beari ng tumors established for 3 days did not have consistent antitumor act ivity, a profound therapeutic effect was observed when IL-12 administr ation was combined with a recombinant vaccinia virus (rVV) encoding be ta-gal called VJS6. On the basis of the reported synergistic effects o f IL-12 and the costimulatory molecule B7-1 (CD80) in vitro, we immuni zed mice with a double recombinant vaccinia encoding both the model tu mor Ag and the costimulatory molecule B7-1, designated B7-1 beta-gal r VV. The adjuvant administration of IL-12 after immunization with this virus significantly enhanced survival in tumor-bearing animals, T cell subset depletions demonstrated that the in vivo activity of IL-12 was largely independent of CD4(+) T lymphocytes, whereas the in vivo acti vity of a B7-1 rVV required both CD4(+) and CD8(+) T cells to elicit m aximal therapeutic effect, To our knowledge, this is the first descrip tion of B7-1 and IL-12 cooperation in vivo and represents a novel stra tegy to enhance the efficacy of recombinant anticancer vaccines.