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Cited by 109CAR-T cell therapy researchT-cell and B-cell ImmunologyImmunotherapy and Immune Responses

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

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Rodriguez-Marquez, Paula, Calleja-Cervantes, Maria E., Serrano, Guillermo, Oliver-Caldes, Aina, Palacios-Berraquero, Maria L., Martin-Mallo, Angel, Calviño, Cristina, Español-Rego, Marta +25 more·2022·Science Advances
DOI 10.1126/sciadv.abo0514PMC PMC9524842

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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.

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  • An insufficient number of vector copies may result in low or absent CAR receptor expression, compromising product efficacy.

    “Therapeutic Efficacy: an insufficient number of vector copies may result in low or absent CAR receptor expression, compromising product efficacy [27–30].”

    From Harmonisation of quality control tests for academic production of CAR-T cells: a position paper from the WP-bioproduction of the UNITC consortium (2025) · cites this paper as [27]

    The Results section (page unavailable) reports fewer vector integrations and lower CAR expression in CARLow cells, alongside lower in vitro cytotoxic activity than CARHigh cells. It does not report absent CAR expression from insufficient copies or establish that low copy number compromises clinical product efficacy; its clinical findings instead associate more CARHigh cells with poorer responses. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

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Authors
Rodriguez-Marquez, P., Calleja-Cervantes, M. E., Serrano, G., Oliver-Caldes, A., Palacios-Berraquero, M. L., Martin-Mallo, A., Calviño, C., Español-Rego, M., Ceballos, C., Lozano, T., San Martin-Uriz, P., Vilas-Zornoza, A., Rodriguez-Diaz, S., Martinez-Turrillas, R., Jauregui, P., Alignani, D., Viguria, M. C., Redondo, M., Pascal, M., Martin-Antonio, B., Juan, M., Urbano-Ispizua, A., Rodriguez-Otero, P., Alfonso-Pierola, A., Paiva, B., Lasarte, J. J., Inoges, S., Lopez-Diaz de Cerio, A., San-Miguel, J., Fernandez de Larrea, C., Hernaez, M., Rodriguez-Madoz, J. R., & Prosper, F.
Affiliations
  • Hemato-Oncology Program, Cima Universidad de Navarra, IdiSNA, Pamplona, Spain.
  • Centro de Investigación Médica Aplicada (ES)
  • Department of Hematology, Hospital Clinic de Barcelona, IDIBAPS, Universidad de Barcelona, Barcelona, Spain.
  • Hematology and Cell Therapy Department, Clínica Universidad de Navarra (CUN), Pamplona, Spain.
  • Clinica Universidad de Navarra (ES)
  • Department of Immunology, Hospital Clinic de Barcelona, IDIBAPS, Universidad de Barcelona, Barcelona, Spain.
  • Navarre Institute of Health Research (ES)
  • Hospital Clínic de Barcelona (ES)
  • Hospital Sant Joan de Déu Barcelona (ES)
  • Centro de Investigación Biomédica en Red de Cáncer (ES)
  • Computational Biology Program, Cima Universidad de Navarra, IdiSNA, Pamplona, Spain.
Corresponding author
Serrano, Guillermo
ORCID
Venue
Science Advances
Publisher
American Association for the Advancement of Science (AAAS)
Published
2022-09-30
Volume
8
Issue
39
Pages
eabo0514-eabo0514
ISSN
2375-2548 (ISSN-L)
DOI
10.1126/sciadv.abo0514
PMC
PMC9524842
OpenAlex
W4298109511
Cited by
109
References
67
Citations by year
2026: 21 · 2025: 26 · 2024: 33 · 2023: 22 · 2022: 7
FWCI
9.21
Type
journal article
Language
en
Open access
Licence
cc-by-nc
Locations
  • Science Advances (publishedVersion, cc-by-nc)
  • medRxiv (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
Funders
  • European Commission (754658, 945393)
  • Universidad de Navarra
  • Gobierno de Navarra
  • Instituto de Salud Carlos III (ICI19/00025, RD21/0017, RD21/0017/0009, PI19/00669, ICI19/00069, /00025, RD16/0011/0005)
  • European Regional Development Fund
Topics
  • Health Sciences › Medicine › Oncology › CAR-T cell therapy research
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
Keywords
chimeric antigen receptor T cells, BCMA, traffic density, multiple myeloma, T cell exhaustion, tonic signaling, gene regulatory networks, bone marrow involvement, clinical response, hematologic malignancies, single-cell transcriptomics

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