Spatiotemporal Control of IL-12 Delivery Improves Its Efficacy in Treatment of Solid Tumors

Abstract

Despite renewed interest in IL-12 as a cancer immunotherapy due to its ability to stimulate the adaptive immune system, its short half-life and narrow therapeutic window continues to present challenges for effective delivery. Previous studies with IL-12 have investigated the effects of route of delivery or sustained delivery of the cytokine on its efficacy but are unable to simultaneously investigate the effects of both within the same system. This work seeks to address this gap by utilizing an elastin-like polypeptide (ELP) carrier, which can undergo a thermally triggered phase transition to a gel-like depot, to probe the effects of both sustained release and spatial delivery of IL-12. By conjugating IL-12 with an ELP, this work creates an IL-12-ELP fusion that can be injected intratumorally or subcutaneously to form a sustained-release depot. In a B16F10 murine model, intratumoral injection of a depot-forming IL-12-ELP fusion significantly improved survival compared to free IL-12. IL-12-ELP is retained within the tumor approximately fourfold longer than free IL-12, resulting in higher CD8+ T cell recruitment at the tumor and local concentrations of inflammatory cytokines at Day 2. Taken together, this work provides insights into rational cytokine delivery, the importance of tumor localization, and the benefits of sustained release.