Antitumor efficacy of PD-1 blocking antibody is enhanced through liposomal delivery and myeloid immune modulation.

Abstract

Systemic monoclonal antibody therapy against the PD-1 immune checkpoint (anti-PD1) is efficacious in less than 40% of patients with solid tumors. Beyond T-cells, PD-1 is expressed on myeloid populations such as monocytes, dendritic cells, myeloid progenitors, and tumor-associated macrophages (TAMs) that also have a propensity to interact with nanoparticles. Here, we developed a liposomal anti-PD1 formulation (LAP) to exploit the interaction of lipid nanoparticles with macrophages, aiming to enhance antitumor efficacy. LAP demonstrated efficient antibody conjugation and target binding, a mean particle size of 89 nm, and intravenous administration was associated with rapid but transient elevation of circulating pro-inflammatory cytokines. While conventional anti-PD1 therapy resulted in a modest, but not statistically significant, inhibition of tumor growth compared to vehicle in the B16-F10 melanoma model, LAP significantly reduced tumor growth and improved survival, achieving complete tumor rejection in 67% of mice versus 17% with conventional antibody treatment. LAP remodeled the tumor immunologic milieu towards an immune permissive environment, with significant reduction of pro-tumoral of M2-TAMs, and increased ratio of cytotoxic-to-regulatory T-cell. Myeloid (CD11b+) cell depletion diminished LAP antitumor efficacy without significantly altering pharmacokinetics, indicating a myeloid cell-dependent anticancer mechanism of action. Together with data showing that LAP did not increase systemic toxicities, these findings strongly support the clinical translation of LAP and liposomes as a platform delivery system that can be leveraged to enhance the efficacy of PD-1 blockade.