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

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.

Enhancing Triple Negative Breast Cancer Immunotherapy by ICG‐Templated Self‐Assembly of Paclitaxel Nanoparticles

“…[10][11][12][13][14][15][16] Thus, complementary approaches to enhance the immunogenicity and reverse the ITM remain a formidable challenge for improving immunotherapy of TNBC. [21][22][23][24][25][26] However, combination immu notherapy suffers from the distinct chemophysical properties and incon sistent pharmacokinetic profiles of the different immune modulators. [21][22][23][24][25][26] However, combination immu notherapy suffers from the distinct chemophysical properties and incon sistent pharmacokinetic profiles of the different immune modulators.…”

Design of a Multicompartment Hydrogel that Facilitates Time‐Resolved Delivery of Combination Therapy and Synergized Killing of Glioblastoma

“…[3] It follows that developing singular materials that can deliver multiple drugs at differing rates should accompany current drug discovery efforts to identify promising new combination therapies. [4] Herein, we develop a syringe-deliverable, self-assembled multicompartment hydrogel platform called ‘Sequogel’ that allows the time-staggered release of small molecule combination therapy and demonstrate its utility in affecting apoptosis in glioblastoma cells in a synergistic manner, Figure 1. We chose glioblastoma as a model system because it is one of the most aggressive forms of brain malignancy with current treatment protocols affording median survival rates of only 18 months.…”

Engineering Biomaterials to Direct Innate Immunity

“…[64] This increase in PD-L1 on APCs makes the cells responsive to checkpoint blockade therapy, where antibodies blocking PD-L1 reestablish the immune at-tack on tumor cells. This approach led to innate activation and increased expression of PD-L1 in tumor-resident APCs.…”