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

Menée à l'aide de lignées cellulaires, de modèles murins et d'échantillons tumoraux issus de patients atteints d'un myélome multiple, cette étude démontre que la densité des récepteurs antigéniques chimériques influence l'efficacité des lymphocytes CAR-T ciblant l'antigène de maturation des lymphocytes B et met en évidence une corrélation entre cette densité et les résultats cliniques

Résumé en anglais

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 CARHigh T cells, providing mechanistic insights behind differential functionality of these cells. Last, we demonstrate that patients treated with CAR T cell products enriched in CARHigh 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. High CAR molecule density affects CAR T cell activity and is associated with impaired clinical response.