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

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 transcripti...

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Bibliographic Details
Authors: Rodríguez Márquez, Paula, Calleja Cervantes, Maria E., Serrano, Guillermo, Oliver Caldés, Aina, Palacios Berraquero, María L., Martín Mallo, Ángel, Calviño Suárez, Cristina, Español Rego, Marta, Ceballos, Candela, Lozano, Teresa, San Martin Uriz, Patxi, Vilas Zornoza, Amaia, Rodríguez Díaz, Saray, Martínez Turrillas, Rebeca, Jáuregui, Patricia, Alignani, Diego, Viguria, María C., Redondo, Margarita, Pascal i Capdevila, Mariona, Martín-Antonio, Beatriz, Juan, Manel, Urbano Ispizua, Álvaro, Rodríguez Otero, Paula, Alfonso Pierola, Ana, Paiva, Bruno, Lasarte, Juan J., Inogés, Susana, López Díaz de Cerio, Ascensión, San Miguel, Jesús, Fernández de Larrea Rodríguez, Carlos José, Hernáez, Mikel, Rodríguez Madoz, Juan R., Prosper, Felipe
Format: article
Status:Published version
Publication Date:2023
Country:España
Institution:Universidad de Barcelona
Repository:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/209150
Online Access:https://hdl.handle.net/2445/209150
Access Level:Open access
Keyword:Cèl·lules T
Mieloma múltiple
T cells
Multiple myeloma
Description
Summary: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.

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