Oral delivery of anti-PD-L1 antibody for cancer immunotherapy against orthotopic colorectal tumors

Despite the approval of immune checkpoint blockade (ICB) for colorectal cancer treatment, its objective response rate remains to be improved, especially for non-immunogenic tumors. Moreover, systemically administrated ICB antibodies is usually associated with immune-related adverse effects (irAEs). Herein, we report novel oral administration of anti-programmed cell death protein L1 (anti-PD-L1) complexes for immunotherapy against colorectal tumors. Antibodies could form nanocomplexes with fluorocarbon modified chitosan (FCS) to acquire greatly improved transmucosal penetration ability, owing to the ability of FCS to reduce mucus binding and temporary open tight junctions between epithelial cells. As evidenced in orthotopic colorectal tumors on mice, orally administrated FCS/anti-PD-L1 nanocomplexes exhibited greatly improved intestinal permeability and significant intertumoral penetration, and if combined with oxaliplatin (OXA) chemotherapy to induce an immunogenic tumor phenotype, could finally inhibit the growth of tumors and prolong the animal survival. Notably, compared to systematic injection of anti-PD-L1, oral administration of FCS/anti-PD-L1 achieved comparable therapeutic efficacy with five-fold dosage, and exhibited reduced tendency of systemic irAEs as exhibited by the decreased percentage of Th17 cells in lymph nodes. Our work here provides a simple but effective strategy for immunotherapy by oral admin-istration of ICB antibodies, achieving strong antitumor immune responses without the concern of systemic irAEs.(c) 2023 Elsevier Ltd. All rights reserved.

Automated summary

This study presents a novel strategy for immunotherapy against colorectal tumors using orally administered anti-PD-L1 complexes. The complexes exhibited improved intestinal permeability and intertumoral penetration, and when combined with oxaliplatin chemotherapy, they inhibited tumor growth and prolonged animal survival. Oral administration achieved comparable therapeutic efficacy with reduced systemic immune-related adverse effects compared to systemic injection. This work provides a simple but effective approach for immunotherapy.