Cancer Therapy: Preclinical Systemic Administration of a Novel Immune-Stimulatory Pseudovirion Suppresses Lung Metastatic Melanoma by Regionally Enhancing IFN-g Production

Purpose: Cancer immunotherapy has encountered many difficulties in the face of the expectation to eradicate cancer, and new breakthroughs are required. We have previously shown that UV-inactivated Sendai virus particles (hemagglutinating virus of Japan envelope; HVJ-E) induce immunity againstmultiple tumor types. In this study, a novel pseudovirion that stimulates more robust antitumor immunity was designed for cancer treatment. ExperimentalDesign: First,we found that culturingmurine splenocyteswithHVJ-E in combinationwith interleukin (IL)-12 resulted in a remarkable increase in IFN-g production compared with that observed in splenocytes cultured with IL-12 alone. The synergistic effects of HVJ-E and IL-12 on IFN-g production were caused by viral F proteins independently of HVJ-E fusion activity and not by hemagglutination from hemagglutinin-neuraminidase (HN) proteins. We next constructed HN-depleted HVJ-E expressing the Fc region of immunoglobulin G (IgG) on the envelope and single-chain IL-12 containing the ZZ domain of protein A to produce an IL-12–conjugated HVJ-E particle without hemagglutinating activity. Results: IL-12–conjugatedHVJ-E dramatically enhanced the amountof IFN-g producedby immune cells. Intratumoral injection of IL-12–conjugated HVJ-E eradicated murine melanomas more effectively than injection of wild-type HVJ-E through increased production of melanoma-specific CTLs. IL-12–conjugated HVJ-E preferentially accumulated in the lungs after systemic administration. When small metastatic melanoma foci were formed in the lungs, systemic administration of IL-12–conjugated HVJ-E significantly reduced the number of metastatic foci by inducing local production of IFN-g in the lungs and generating large numbers of melanoma-specific CTLs. Conclusion: IL-12–conjugated HVJ-E is a promising tool for the treatment of cancers, including lung metastasis. Clin Cancer Res; 19(3); 668–79. 2012 AACR.