Intratumoral IL-18 gene transfer improves therapeutic efficacy of antibody-targeted superantigen in established murine melanoma

Antibody-targeted superantigen C215Fab-SEA is a fusion protein of staphylococcal enterotoxin A (SEA) and the Fab region of the tumor-reactive C215 mAb. It can trigger CTL against C215 antigen-positive tumor cells and induce tumor-suppressive cytokines. However, the antitumor effect of C215Fab-SEA is not satisfactory because of suboptimal production of Th1 cytokines after repeated administration. Interleukin 18 (IL-18) is a novel cytokine with profound effects on Th1 cellular response. In this study, we showed that adenovirus-mediated intratumoral IL-18 gene transfer strongly improved the therapeutic efficacy of C215Fab-SEA in the pre-established C215 antigen-expressing B16 melanoma murine model. More significant tumor inhibition and prolonged survival time were observed in tumor-bearing mice received combined therapy of C215Fab-SEA and Ad IL-18 than those of mice treated with C215Fab-SEA or AdIL-18 alone. Combination therapy augmented NK and CTL activities of tumor-bearing mice more markedly. The production of IL-2 and IFN-γ also increased more significantly. More potent antitumor effect of combined therapy was observed in IL-10 KO mice with enhanced Th1 response. Our data demonstrated that the antitumor effect of C215Fab-SEA immunotherapy could be potentiated significantly by combination with intratumoral IL-18 gene transfer through more efficient activation of Th1 immune responses.