CAR density influences antitumoral efficacy of BCMA CAR T cells and correlates with clinical outcome

Abstract

Identification of new markers associated with long-term efficacy in patients treated with CAR T cells is a current medical need, particularly in diseases such as multiple myeloma. In this study, we address the impact of CAR density on the functionality of BCMA CAR T cells.

Functional and transcriptional studies demonstrate that CAR T cells with high expression of the CAR construct show an increased tonic signaling with up-regulation of exhaustion markers and increased in vitro cytotoxicity but a decrease in in vivo BM infiltration.

Characterization of gene regulatory networks using scRNA-seq identified regulons associated to activation and exhaustion up-regulated in CAR^High T cells, providing mechanistic insights behind differential functionality of these cells. Last, we demonstrate that patients treated with CAR T cell products enriched in CAR^High T cells show a significantly worse clinical response in several hematological malignancies.

In summary, our work demonstrates that CAR density plays an important role in CAR T activity with notable impact on clinical response.

CITATION  Sci Adv. 2022 Sep 30;8(39):eabo0514.  doi: 10.1126/sciadv.abo0514