Publicaciones científicas

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

30-sep-2022 | Revista: 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.

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