Synthetic Polymers To Address Multiscale Drug Delivery Challenges For Cancer Immunotherapy

Abstract

Immunotherapy has revolutionized cancer treatment, yet its clinical impact is limited by toxicity and/or low therapeutic response in many different tumor types. Eliciting optimal spatiotemporal antitumor immune responses is crucial to overcoming this hurdle, but is complicated by multiscale drug delivery challenges to immune activators. This work utilizes targeted, bioresponsive synthetic polymeric drug delivery platforms to address these challenges in engineering next-generation cancer immunotherapies. First, we adapted the Virus-Inspired Polymer for Endosomal Release (VIPER) platform to cytosolically deliver peptide antigens to lymphatic dendritic cells (DCs) for cancer vaccination. Co-polymerized mannose ligands confer lymph node targeting and DC internalization, while the VIPER design selectively lyses maturing endosome to release peptide antigens into the cytosol. This induces superior cytotoxic T-cell activation and tumor suppression compared to simple peptide vaccines and non-endosome releasing designs. Next, we engineered a targeted polymeric prodrug of Stimulator of Interferon Genes (STING) agonist for targeted immune activation in DCs in an intravenous immunotherapy application. A STING agonist is formulated into a monomer with an endosomal cathepsin-labile linker, and co-polymerized with mannose to form a STING ‘drugamer’ (polySTING) that selectively delivers agonist to DCs. Intravenous polySTING administration results in a DC-driven immune cascade that potently suppresses tumor growth in aggressive murine tumor models. Structural variants of STING drugamers were then co-formulated with VIPER to yield two distinct STING-adjuvanted polymeric vaccines that achieved partial remission through distinct antitumor immunity mechanisms. Finally, a T-cell-targeted cationic brush polymer platform is being developed for T-cell transfection for Chimeric Antigen Receptor (CAR) T-cell production.