In addition, factors related to CAR structure, such as the costimulatory domain or the hinge length, can also affect the antitumoral potential of CAR T cells ( 10– 12). Several studies have demonstrated how extrinsic factors, such as antigen density or tumor burden, strongly influence efficacy of CAR T cells ( 8, 9). It is well known that CAR T cells are heterogeneous products with multiple factors contributing to their efficacy. In summary, our work demonstrates that CAR density plays an important role in CAR T activity with notable impact on clinical response. 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. 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. 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. In this study, we address the impact of CAR density on the functionality of BCMA CAR T cells. 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. Rodriguez-Madoz, and Felipe Prosper Show Fewer Lasarte, Susana Inoges, Ascension Lopez-Diaz de Cerio, Jesus San-Miguel, Carlos Fernandez de Larrea, Mikel Hernaez, Juan R. Viguria, Margarita Redondo, Mariona Pascal, Beatriz Martin-Antonio, Manel Juan, Alvaro Urbano-Ispizua, Paula Rodriguez-Otero, Ana Alfonso-Pierola, Bruno Paiva, Juan J. Palacios-Berraquero, Angel Martin-Mallo, Cristina Calviño, … Show All …, Marta Español-Rego, Candela Ceballos, Teresa Lozano, Patxi San Martin-Uriz, Amaia Vilas-Zornoza, Saray Rodriguez-Diaz, Rebeca Martinez-Turrillas, Patricia Jauregui, Diego Alignani, Maria C. Calleja-Cervantes, Guillermo Serrano, Aina Oliver-Caldes, Maria L.
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