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author Rodriguez-Marquez, Paula
Calleja-Cervantes, Maria E.
Serrano, Guillermo
Oliver-Caldes, Aina
Palacios-Berraquero, Maria L.
Martin-Mallo, Angel
Calviño, Cristina
Español-Rego, Marta
Ceballos, Candela
Lozano, Teresa
San Martin-Uriz, Patxi
Vilas-Zornoza, Amaia
Rodriguez-Diaz, Saray
Martinez-Turrillas, Rebeca
Jauregui, Patricia
Alignani, Diego
Viguria, Maria C.
Redondo, Margarita
Pascal, Mariona
Martin-Antonio, Beatriz
Juan, Manel
Urbano-Ispizua, Alvaro
Rodriguez-Otero, Paula
Alfonso-Pierola, Ana
Paiva, Bruno
Lasarte, Juan J.
Inoges, Susana
Lopez-Diaz de Cerio, Ascension
San-Miguel, Jesus
Fernandez de Larrea, Carlos
Hernaez, Mikel
Rodriguez-Madoz, Juan R.
Prosper, Felipe
author_facet Rodriguez-Marquez, Paula
Calleja-Cervantes, Maria E.
Serrano, Guillermo
Oliver-Caldes, Aina
Palacios-Berraquero, Maria L.
Martin-Mallo, Angel
Calviño, Cristina
Español-Rego, Marta
Ceballos, Candela
Lozano, Teresa
San Martin-Uriz, Patxi
Vilas-Zornoza, Amaia
Rodriguez-Diaz, Saray
Martinez-Turrillas, Rebeca
Jauregui, Patricia
Alignani, Diego
Viguria, Maria C.
Redondo, Margarita
Pascal, Mariona
Martin-Antonio, Beatriz
Juan, Manel
Urbano-Ispizua, Alvaro
Rodriguez-Otero, Paula
Alfonso-Pierola, Ana
Paiva, Bruno
Lasarte, Juan J.
Inoges, Susana
Lopez-Diaz de Cerio, Ascension
San-Miguel, Jesus
Fernandez de Larrea, Carlos
Hernaez, Mikel
Rodriguez-Madoz, Juan R.
Prosper, Felipe
author_sort Rodriguez-Marquez, Paula
collection PubMed
description 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.
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spelling pubmed-95248422022-10-13 CAR density influences antitumoral efficacy of BCMA CAR T cells and correlates with clinical outcome Rodriguez-Marquez, Paula Calleja-Cervantes, Maria E. Serrano, Guillermo Oliver-Caldes, Aina Palacios-Berraquero, Maria L. Martin-Mallo, Angel Calviño, Cristina Español-Rego, Marta Ceballos, Candela Lozano, Teresa San Martin-Uriz, Patxi Vilas-Zornoza, Amaia Rodriguez-Diaz, Saray Martinez-Turrillas, Rebeca Jauregui, Patricia Alignani, Diego Viguria, Maria C. Redondo, Margarita Pascal, Mariona Martin-Antonio, Beatriz Juan, Manel Urbano-Ispizua, Alvaro Rodriguez-Otero, Paula Alfonso-Pierola, Ana Paiva, Bruno Lasarte, Juan J. Inoges, Susana Lopez-Diaz de Cerio, Ascension San-Miguel, Jesus Fernandez de Larrea, Carlos Hernaez, Mikel Rodriguez-Madoz, Juan R. Prosper, Felipe Sci Adv Biomedicine and Life Sciences 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. American Association for the Advancement of Science 2022-09-30 /pmc/articles/PMC9524842/ /pubmed/36179026 http://dx.doi.org/10.1126/sciadv.abo0514 Text en Copyright © 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC). https://creativecommons.org/licenses/by-nc/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license (https://creativecommons.org/licenses/by-nc/4.0/) , which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.
spellingShingle Biomedicine and Life Sciences
Rodriguez-Marquez, Paula
Calleja-Cervantes, Maria E.
Serrano, Guillermo
Oliver-Caldes, Aina
Palacios-Berraquero, Maria L.
Martin-Mallo, Angel
Calviño, Cristina
Español-Rego, Marta
Ceballos, Candela
Lozano, Teresa
San Martin-Uriz, Patxi
Vilas-Zornoza, Amaia
Rodriguez-Diaz, Saray
Martinez-Turrillas, Rebeca
Jauregui, Patricia
Alignani, Diego
Viguria, Maria C.
Redondo, Margarita
Pascal, Mariona
Martin-Antonio, Beatriz
Juan, Manel
Urbano-Ispizua, Alvaro
Rodriguez-Otero, Paula
Alfonso-Pierola, Ana
Paiva, Bruno
Lasarte, Juan J.
Inoges, Susana
Lopez-Diaz de Cerio, Ascension
San-Miguel, Jesus
Fernandez de Larrea, Carlos
Hernaez, Mikel
Rodriguez-Madoz, Juan R.
Prosper, Felipe
CAR density influences antitumoral efficacy of BCMA CAR T cells and correlates with clinical outcome
title CAR density influences antitumoral efficacy of BCMA CAR T cells and correlates with clinical outcome
title_full CAR density influences antitumoral efficacy of BCMA CAR T cells and correlates with clinical outcome
title_fullStr CAR density influences antitumoral efficacy of BCMA CAR T cells and correlates with clinical outcome
title_full_unstemmed CAR density influences antitumoral efficacy of BCMA CAR T cells and correlates with clinical outcome
title_short CAR density influences antitumoral efficacy of BCMA CAR T cells and correlates with clinical outcome
title_sort car density influences antitumoral efficacy of bcma car t cells and correlates with clinical outcome
topic Biomedicine and Life Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9524842/
https://www.ncbi.nlm.nih.gov/pubmed/36179026
http://dx.doi.org/10.1126/sciadv.abo0514
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