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In Science advances

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.

Rodriguez-Marquez Paula, Calleja-Cervantes Maria E, Serrano Guillermo, Oliver-Caldes Aina, Palacios-Berraquero Maria L, Martin-Mallo Angel, Calviño Cristina, Español-Rego Marta, Ceballos Candela, Lozano Teresa, San Martin-Uriz Patxi, Vilas-Zornoza Amaia, Rodriguez-Diaz Saray, Martinez-Turrillas Rebeca, Jauregui Patricia, Alignani Diego, Viguria Maria C, Redondo Margarita, Pascal Mariona, Martin-Antonio Beatriz, Juan Manel, Urbano-Ispizua Alvaro, Rodriguez-Otero Paula, Alfonso-Pierola Ana, Paiva Bruno, Lasarte Juan J, Inoges Susana, Lopez-Diaz de Cerio Ascension, San-Miguel Jesus, Fernandez de Larrea Carlos, Hernaez Mikel, Rodriguez-Madoz Juan R, Prosper Felipe