Abstract 3462: Novel delivery platform for temporally-controlled release of immunocytokines and immune checkpoint inhibitors to enhance cancer therapy

Abstract Interleukin-2 (IL-2) is a multifunctional cytokine that plays a critical role in the differentiation, proliferation, activation, and survival of immune cells and has been used therapeutically for over 30 years as a cancer treatment. Unfortunately, the cytokine’s narrow therapeutic window and its short circulation half-life have severely limited its clinical application. Strategies designed to bias the activities of IL-2 represent emergent and promising avenues in the treatment of cancer, as they afford the opportunity to selectively target and stimulate certain immune cell subtypes. Recently, our lab has developed one such therapy, termed an immunocytokine (IC), which fuses IL-2 to an anti-IL-2 antibody that biases the cytokine towards immunostimulatory activities while also extending its persistence in the bloodstream. Additionally, we further established that the IC was able to synergize with immune checkpoint inhibitors (ICIs) to effectively clear tumors through expansion of CD8+ T cells and stimulation of their effector functions. Interestingly, it was observed that the therapeutic effects of this combination treatment were highly sensitive to dosing regimen; specifically, robust antitumor activity was observed when IC was delivered after ICI, but not when the order was reversed. Building on this observation of time-dependent anti-cancer activity, here we expand upon this work through the development of a biomaterial system that will enable further exploration of the kinetics surrounding the combinatorial delivery landscape using IC and ICIs. Our biomaterial system involves formulation of nanoparticles that encapsulate IC and ICIs using a flash nano complexation and flash nanoprecipitation system. These particles are further enclosed within a hydrogel system for protection and sustained release within the tumor environment, controlling both the temporal and spatial distribution of the encapsulated immunotherapies. We have successfully designed and characterized the delivery platform and established time-dependent release of the therapeutic cargo. In vivo immune stimulation and tumor clearance studies are ongoing to further evaluate our approach. Overall, our work introduces an innovative and highly versatile bioengineering approach that can be tuned to optimize immunotherapy strategies in a wide range of cancer types. Citation Format: Pilar O'Neal, Julia Lu, Yicheng Zhang, Marek Kovar, Hai-Quan Mao, Jamie Spangler. Novel delivery platform for temporally-controlled release of immunocytokines and immune checkpoint inhibitors to enhance cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3462.