Mechanostimulatory Platform for Improved CAR T Cell Immunotherapy.

Abstract

Chimeric Antigen Receptor T (CAR T) cell immunotherapy has revolutionized cancer treatment, yet it is hindered by rapid T-cell exhaustion caused by uncontrolled activation during CAR generation. Leveraging insights into T-cell mechanosensing, a novel mechanostimulatory platform is engineered for T-cell activation based on an antigen-carrying surface with controlled elasticity and nanotopography. The platform is designed to optimize and balance T-cell exhaustion, proliferation, and CAR expression. It enhances the differentiation of T cells into the central memory subset, which is crucial for the persistence of CAR T cell therapy's anticancer effects. The platform produces CAR T cells with higher antitumor efficacy, as validated through ex vivo experiments, and with higher in vivo persistence and ability to suppress tumor proliferation, as compared to CAR T cells generated by standard protocols. RNA-seq analysis confirmed an increased transcriptional signature of central memory T cells. Furthermore, this platform completely eliminates T-cell toxicity associated with the non-viral transfection process typically observed with standard activation methods. This platform presents a promising pathway for improving the efficiency and safety of CAR T cell therapy.