Scientific publications

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

Sep 30, 2022 | Magazine: Science Advances

Paula Rodriguez-Marquez  1 , Maria E Calleja-Cervantes  1   2 , Guillermo Serrano  2 , Aina Oliver-Caldes  3 , Maria L Palacios-Berraquero  4 , Angel Martin-Mallo  1 , Cristina Calviño  4 , Marta Español-Rego  5 , Candela Ceballos  6 , Teresa Lozano  7 , Patxi San Martin-Uriz  1 , Amaia Vilas-Zornoza  1   8 , Saray Rodriguez-Diaz  1 , Rebeca Martinez-Turrillas  1   8 , Patricia Jauregui  4 , Diego Alignani  9 , Maria C Viguria  6 , Margarita Redondo  6 , Mariona Pascal  5 , Beatriz Martin-Antonio  3 , Manel Juan  5   10 , Alvaro Urbano-Ispizua  3 , Paula Rodriguez-Otero  4 , Ana Alfonso-Pierola  4   8 , Bruno Paiva  1   8   9 , Juan J Lasarte  7 , Susana Inoges  4   8   11 , Ascension Lopez-Diaz de Cerio  4   8   11 , Jesus San-Miguel  1   4   8   12 , Carlos Fernandez de Larrea  3 , Mikel Hernaez  2   8   13 , Juan R Rodriguez-Madoz  1   8 , Felipe Prosper  1   4   8   12


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 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.

CITATION  Sci Adv. 2022 Sep 30;8(39):eabo0514.  doi: 10.1126/sciadv.abo0514

Our authors

Juan Roberto Rodríguez Madoz
Mikel
Researcher | Principal Investigator Computational Biology Program
Paula Rodríguez Márquez
Mª Erendira Calleja Cervantes
Bioinformatics Research Technician Adoptive Cellular Therapy Research Group
Senior Researcher | Principal Investigator Multiple Myeloma Research Group
Guillermo Serrano Sanz
Bioinformatics Research Technician Bioinformatics Platform
Ángel Martín Mallo
Patxi San Martín Uriz
Project Researcher Multiple Myeloma Research Group
Saray Rodríguez Díaz
Rebeca Martínez Turrillas
Diego Alignani
Senior Research Technician Cytometry Platform
Researcher | Principal Investigator Peptide Research Group