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 staphyloc occal 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 t umor-suppressive cytokines. However, the antitumor effect of C215Fab-SEA is not satisfactory because of suboptimal production of Th1 cytokines after r epeated administration. Interleukin 18 (IL-18) is a novel cytokine with pro found effects on Th1 cellular response. in this study, we showed that adeno virus-mediated intratumoral IL-18 gene transfer strongly improved the thera peutic efficacy of C215Fab-SEA in the pre-established C215 antigen-expressi ng B16 melanoma murine model. More significant tumor inhibition and prolong ed survival time were observed in tumor-bearing mice received combined ther apy 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 t umor-bearing mice more markedly. The production of IL-2 and IFN-gamma also increased more significantly. More potent antitumor effect of combined ther apy was observed in IL-10 KO mice with enhanced Th1 response. Our data demo nstrated that the antitumor effect of C215Fab-SEA immunotherapy could be po tentiated significantly by combination with intratumoral IL-18 gene transfe r through more efficient activation of Th1 immune responses.