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

Authors :
Paula Rodriguez-Marquez
Maria E. Calleja-Cervantes
Guillermo Serrano
Aina Oliver-Caldes
Maria L. Palacios-Berraquero
Angel Martin-Mallo
Cristina Calviño
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. Viguria
Margarita Redondo
Mariona Pascal
Beatriz Martin-Antonio
Manel Juan
Alvaro Urbano-Ispizua
Paula Rodriguez-Otero
Ana Alfonso-Pierola
Bruno Paiva
Juan J. Lasarte
Susana Inoges
Ascension Lopez-Diaz de Cerio
Jesus San-Miguel
Carlos Fernandez de Larrea
Mikel Hernaez
Juan R. Rodriguez-Madoz
Felipe Prosper
Source :
Science Advances. 8
Publication Year :
2022
Publisher :
American Association for the Advancement of Science (AAAS), 2022.

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.

Subjects

Subjects :
Multidisciplinary

Details

ISSN :
23752548
Volume :
8
Database :
OpenAIRE
Journal :
Science Advances
Accession number :
edsair.doi.dedup.....9b4d5aef60ed3ce12d8e6ee7288a7dbd
Full Text :
https://doi.org/10.1126/sciadv.abo0514