Conditional interleukin-12 gene therapy promotes safe and effective antitumor immunity

摘要

We and others have previously demonstrated that (chronic) interleukin (IL)-12 gene therapy delivered intratumorally through ex vivo gene-engineered dendritic cell (DC) is competent to promote the regression of established murine tumors. In this report, we have developed a conditional expression system (rAd.RheoIL12) to determine the temporal requirements of transgenic IL-12p70 production by administered DC on therapeutic outcome in a subcutaneous B16 melanoma model. DCs infected with rAd.RheoIL12 (DC.RheoIL12) secreted IL-12p70 in a tightly regulated fashion in response to a synthetic diacylhydrazine small molecule ligand in vitro, and the treatment benefit of DC.RheoIL12 delivered into B16 lesions was strictly ligand dependent in vivo. Indeed, DC.RheoIL12-based therapy promoted the regression of established day 7 B16 tumor lesions after intratumoral injection, provided that ligand administration occurred within 24?h of DC injection and was sustained for approximately 5 or more days. Treatment efficacy was correlated to the magnitude of systemic anti-B16 CD8+ T cells cross-primed in vivo, which in turn, appeared dependent on the early enhanced in vivo survival of adoptively transferred DC.RheoIL12 in tumor and tumor-draining lymph nodes. The unique safety feature of DC.RheoIL12 application was emphasized in a combined treatment model with rIL-2, where profound TNF-α-associated toxicity could be ameliorated upon discontinuation of activating ligand administration.