Abstract 1791: An injectable depot technology for sustained locoregional delivery improves the efficacy and safety of immunotherapies and adoptive cell therapies

Abstract Advances in immunotherapy have revolutionized care for cancer patients. Unfortunately, many approaches fail to mount a robust anti-cancer effect, in part due to the highly immunosuppressive tumor microenvironment in solid tumors. Similarly, while adoptive cell therapies (ACT) like CAR-T therapies have demonstrated immense potential in treating various B cell malignancies, they have been less successful in treating solid tumors on account of the immunosuppressive environment. To address these challenges, the field has turned to either combination immunotherapies or locoregional delivery of therapies as systemic administration of potent therapies can result in severe immune related adverse effects. Enabling potent combination immunotherapies requires administering these immune agonists in a way that more closely resembles the endogenous cancer immunity cycle, a tightly regulated sequence of cues in both space and time. Here, we will discuss the development of an injectable hydrogel depot technology for rational localization and prolonged exposure of potent immunotherapeutic cytokines (IL-12, IL-2), antibodies (OX40a, PD1), and ACTs to improve these therapies. Specifically, we have developed a self-assembled polymer-nanoparticle (PNP) hydrogel system that is both highly shear-thinning and rapidly self-healing, enabling minimally invasive implantation though direct injection or catheter delivery to tissues. First we will discuss how these hydrogels enable targeted delivery of immunomodulatory cargo either intratumorally (IT) or peritumorally (PT). We hypothesized that selectively altering biodistribution would more effectively augment the immune response more than sustained locoregional delivery alone. Using in vivo imaging, we demonstrated that site of administration is critical to redistributing cargo to either the tumor or tumor draining lymph node (tdLN). In this way we demonstrated that targeted localization of cytokine and antibody therapies synergistically improved treatment efficacy in the B16F10 and MC38 tumor models and altered cellular phenotypes in these microenvironments. Second we will discuss how these hydrogels enable the controlled co-delivery of stimulatory cytokines and adoptive cells to improve treatment of solid tumors. The unique architecture of these materials simultaneously enables prolonged retention of entrapped cytokines while maintaining active motility of entrapped cells. Upon administration this hydrogel depot forms a transient inflammatory niche that induces more tumor-reactive phenotypes and sustains exposure of activated adoptive cells, thereby improving treatment efficacy. Overall, this presentation will discuss how PNP hydrogels represent a crucial new tool for improving therapeutic efficacy of immunotherapies and adoptive cell therapies for cancer. Citation Format: Eric A. Appel. An injectable depot technology for sustained locoregional delivery improves the efficacy and safety of immunotherapies and adoptive cell therapies [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 1791.