In situ formed reactive oxygen species–responsive scaffold with gemcitabine and checkpoint inhibitor for combination therapy

TLDR

Patients with low‑immunogenic tumors respond poorly to immune checkpoint blockade targeting the PD‑1/PD‑L1 pathway, while responders can experience side effects. We engineered an in‑situ forming scaffold that locally releases gemcitabine and an anti‑PD‑L1 antibody with distinct release kinetics. The scaffold is a ROS‑degradable hydrogel that releases therapeutics in a programmed manner within the ROS‑rich tumor microenvironment. The aPDL1‑GEM scaffold induced an immunogenic tumor phenotype, promoted immune‑mediated regression, and prevented recurrence after primary resection in tumor‑bearing mice.

Abstract

Patients with low-immunogenic tumors respond poorly to immune checkpoint blockade (ICB) targeting the programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) pathway. Conversely, patients responding to ICB can experience various side effects. We have thus engineered a therapeutic scaffold that, when formed in situ, allows the local release of gemcitabine (GEM) and an anti-PD-L1 blocking antibody (aPDL1) with distinct release kinetics. The scaffold consists of reactive oxygen species (ROS)-degradable hydrogel that releases therapeutics in a programmed manner within the tumor microenvironment (TME), which contains abundant ROS. We found that the aPDL1-GEM scaffold elicits an immunogenic tumor phenotype and promotes an immune-mediated tumor regression in the tumor-bearing mice, with prevention of tumor recurrence after primary resection.