Intratumoral coinjection of two adenoviruses, one encoding the chemokine IFN-gamma-Inducible protein-10 and another encoding IL-12, results in markedantitumoral synergy

We have constructed a recombinant defective adenovirus that expresses funct ional murine IFN-gamma-inducible protein-10 (IP-10) chemokine (AdCMVIP-10). Injection of AdCMVIP-10 into s.c. tumor nodules derived from the CT26 muri ne colorectal adenocarcinoma cell line displayed some antitumor activity bu t IL was not curative in most cases. Previous studies have shown that injec tion of similar s.c. CT26 tumor nodules with adenovirus-encoding IL-12 (AdC MVIP-12) induces tumor regression in nearly 70% of cases in association wit h generation of antitumor CTL activity. AdCMVIP-10 synergizes with the anti tumor effect of suboptimal doses of AdCMVIL-12, reaching 100% of tumor erad ication not only against injected, but also against distant noninjected tum or nodules. Colocalization of both adenoviruses at the sametumor nodule was required for the local and distant therapeutic effects. Importantly, intra tumoral gene transfer with IL-12 and IP-10 generated a powerful tumor-speci fic CTL response in a synergistic fashion, while both CD4 and CD8 T cells a ppeared in the infiltrate of regressing tumors. Moreover, the antitumor act ivity of IP-10 plus IL-12 combined gene therapy was greatly diminished by s imultaneous in vivo depletion of CD4(+) and CD8(+) T cells but was largely unaffected by single depletion of each T cell subset. An important role for NK cells was also suggested by asialo GM1 depletion experiment. From a cli nical point of view, the effects of IP-10 permit one to lower the required gene transfer level of IL-12, thus preventing dose-dependent IL-12-mediated toxicity while improving the therapeutic efficacy of the elicited antitumo r response.