Key role of CD4+ T cells in determining CD8 function during CAR-T cell manufacture

Abstract

T-cell- Based immunotherapies have revolutionized the treatment landscape of blood cancers. Introduced into the clinic in the last decade, chimeric antigen receptor (CAR)-T cells have shown remarkable efficacy in relapsed and refractory B cell malignancies. In pursuing standardized CAR-T cell production, multiple groups have chosen to premanufacture T cells through selective culture of CD4+ and CD8+ T cells. These cells are separately grown, engineered with the CAR, and administered to patients. In this issue of the Journal of ImmunoTherapy, Lee et al at the Fred Hutchinson center in Seattle, USA, report on the suboptimal expansion and reduced functionality in CD8+CAR T cells when grown in the absence of CD4+T cells, prompting further investigation that culminated in their paper. Their research demonstrates that the successful production of functional, memory CD8+CAR T cells is significantly dependent on the activation of CD4+T cells during CAR-T cell generation. Notably, CD8+CAR T cells produced without CD4+T cells displayed signs of dysfunction, both transcriptionally and immunophenotypically. The paper also reveals key molecules involved in this interaction. This work highlights the crucial role of T cell help in the functionality of CD8+T cells, especially in contexts lacking antigen-presenting cells.