Chimeric antigen receptor with novel intracellular modules improves antitumor performance of T cells

Chimeric antigen receptor with novel intracellular modules improves antitumor performance of T cells

Blog Article

Abstract The excessive cytokine release and limited persistence represent major challenges for chimeric read more antigen receptor T (CAR-T) cell therapy in diverse tumors.Conventional CARs employ an intracellular domain (ICD) from the ζ subunit of CD3 as a signaling module, and it is largely unknown how alternative CD3 chains potentially contribute to CAR design.Here, we obtained a series of CAR-T cells against HER2 and mesothelin using a domain comprising a single immunoreceptor tyrosine-based activation motif from different CD3 subunits as the ICD of CARs.While these reconstituted CARs conferred sufficient antigen-specific cytolytic activity on equipped T cells, they elicited low tonic signal, ameliorated the exhaustion and promoted memory differentiation of these cells.Intriguingly, the CD3ε-derived ICD outperformed others in generation of CAR-T cells that produced minimized cytokines.

Mechanistically, CD3ε-based CARs displayed a restrained cytomembrane expression on engineered T cells, which was ascribed to endoplasmic reticulum retention mediated 6-0 igora vibrance by the carboxyl terminal basic residues.The present study demonstrated the applicability of CAR reconstitution using signaling modules from different CD3 subunits, and depicted a novel pattern of CAR expression that reduces cytokine release, thus paving a way for preparation of CAR-T cells displaying improved safety and persistence against diverse tumor antigens.