(592c) Biomaterial Nanoparticles Redistribute Therapeutic Antibodies to Lymph Node-Resident Cells to Enhance Cancer Immunotherapy Via Checkpoint Inhibition

Immunotherapy has emerged as the most promising new treatment approach for an array of advanced malignancies. In particular, monoclonal antibody (mAb) checkpoint inhibitor drugs are increasingly utilized as cancer immunotherapeutic agents due to their capacity to modulate immune cell signaling to enhance anti-tumor adaptive immunity. Although responses are often durable, a large majority of patients do not respond to such treatments. Furthermore, several treatment-associated toxicities remain to be minimized. Since lymph nodes (LNs) are tissues where adaptive immune responses are initiated and regulated, we hypothesized that targeted delivery to LNs has significant potential to improve the therapeutic effects of immunotherapeutic mAb drugs for cancer immunotherapy. To accomplish this goal, we leveraged ~30 nm nanoparticles (NPs) comprised of a poly(propylene sulfide) core surface stabilized with block co-polymer Pluronics that, by virtue of their formulation and ultrasmall size, exhibit greatly enhanced profiles of lymphatic uptake into lymphatic tissues and accumulation within LNs post administration. Since mAbs require their 3D conformation to recognize cognate antigen, a mild and aqueous phase-based conjugation strategy was employed to maximally preserve the functionality of the mAb Fab. We found NP conjugation did not negatively affect mAb binding capacity and significantly enhanced mAb accumulation within dLN 6-50-fold and lowered accumulation in systemic off-target tissues. Localized immunotherapy utilizing checkpoint inhibitor mAb conjugated to the NP resulted in slowed tumor growth relative to saline-treated controls and animals treated with free mAb administered systemically. Our results suggest lymphatic draining NPs can be used to improve the immunotherapeutic effects of checkpoint blockade therapy.