INTERLEUKIN-12 AND B7-1 COSTIMULATORY MOLECULE EXPRESSED BY AN ADENOVIRUS VECTOR ACT SYNERGISTICALLY TO FACILITATE TUMOR-REGRESSION

Stimulation of antitumor immune mechanisms is the primary goal of canc er immunotherapy, and accumulating evidence suggests that effective al teration of the host-tumor relationship involves immunomodulating cyto kines and also the presence of costimulatory molecules, To examine the antitumor effect of direct in vivo gene transfer of murine interleuki n 12 (IL-12) and B7-1 into tumors, we developed an adenovirus (Ad) vec tor, AdIL12-B7-1, that encodes the two IL-12 subunits in early region 1 (El) and the B7-1 gene in E3 under control of the murine cytomegalov irus promoter, This vector expressed high levels of IL-12 and B7-1 in infected murine and human cell lines and in primary murine tumor cells , In mice bearing tumors derived from a transgenic mouse mammary adeno carcinoma, a single intratumoral injection with a low dose (2.5 x 10(7 ) pfu/mouse) of AdIL12-B7-1 mediated complete regression in 70% of tre ated animals, By contrast, administration of a similar dose of recombi nant virus encoding IL-12 or B7-1 alone resulted in only a delay in tu mor growth, Interestingly, coinjection of two different viruses expres sing either IL-12 or B7-1 induced complete tumor regression in only 30 % of animals treated at this dose, Significantly, cured animals remain ed tumor free after rechallenge with fresh tumor cells, suggesting tha t protective immunity had been induced by treatment with AdIL12-B7-1, These results support the use of Ad vectors as a highly efficient deli very system for synergistically acting molecules and show that the com bination of IL-12 and B7-1 within a single Ad vector might be a promis ing approach for in vivo cancer therapy.