Toroidal-spiral particles as a CAR-T cell delivery device for solid tumor immunotherapy

Area of Science:

• Biomaterials Science
• Immunotherapy
• Oncology

Background:

• Chimeric antigen receptor (CAR) T-cell therapy shows promise for hematologic malignancies but faces challenges in solid tumors, including poor trafficking, toxicity, and antigen escape.
• Current delivery methods for CAR-T cells often result in insufficient tumor infiltration and localized efficacy.

Purpose of the Study:

• To develop and evaluate a novel biodegradable polymeric toroidal-spiral particle (TSP) as an in vivo cell incubator and delivery system for CAR-T cells in solid tumors.
• To assess the efficacy of TSPs for localized delivery and sustained release of mesothelin (MSLN)-specific CAR-T cells in preclinical solid tumor models.

Main Methods:

• Fabrication of millimeter-sized TSPs using crosslinked gelatin methacrylamine (GelMA) and poly(ethylene glycol) diacrylate (PEGDA) with tunable degradation rates.
• Co-encapsulation of collagen and MSLN CAR-T cells within the TSP's void volume for sustained proliferation, activation, and migration.
• Evaluation of TSP-mediated peritumoral delivery of MSLN CAR-T cells in preclinical mouse solid tumor models, comparing outcomes to systemic and intratumoral injections.

Main Results:

• TSPs demonstrated tunable degradation rates and appropriate mechanical properties for sustained release of co-encapsulated compounds.
• The TSPs successfully promoted CAR-T cell proliferation, activation, and migration within the tumor microenvironment.
• Peritumoral delivery of MSLN CAR-T cells via TSPs achieved superior antitumor effects compared to systemic and intratumoral administration in mouse models.

Conclusions:

• Biodegradable TSPs serve as effective in vivo reactors for CAR-T cell expansion and localized delivery.
• TSP-mediated delivery offers a minimally invasive approach to enhance CAR-T cell efficacy against solid tumors while potentially reducing toxicity.
• This innovative delivery system holds promise for improving CAR-T cell therapy outcomes in solid tumor treatment.