Journal
SCIENCE ADVANCES
Volume 8, Issue 39, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.abo0514
Keywords
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Funding
- Instituto de Salud Carlos III - European Regional Development Fund-FEDER A way to make Europe [PI19/00922, PI19/00669, ICI19/00025, ICI19/00069]
- Centro de Investigacion Biomedica en Red de Cancer CIBERONC [CB16/12/00369, CB16/12/00489]
- Ministerio de Ciencia e Innovacion - European Regional Development Fund-FEDER A way to make Europe [RTC-2017-6578-1, PID2019-108989RB-I00]
- European Commission [945393, 754658, 898356]
- Gobierno de Navarra [0011-1411-2020-000011, 0011-1411-2020-000010, 0011-1411-2019-000079, 0011-1411-2019-000072, PC011-012]
- Fundacion La Caixa [CP042702]
- Asociacion Espanola Contra el Cancer-AECC [LABAE21971FERN]
- Paula and Rodger Riney Foundation
- FPU grant from Ministerio de Universidades [FPU19/06160]
- Red de Terapia Celular TERCEL [RD16/0011/0005]
- Red de Terapias Avanzadas TERAV [RD21/0017/0009, RD21/0017/0019]
- Marie Curie Actions (MSCA) [898356] Funding Source: Marie Curie Actions (MSCA)
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This study investigates the impact of CAR density on the functionality and clinical response of BCMA CAR T cells. It found that CAR T cells with high expression of the CAR construct have increased tonic signaling, up-regulation of exhaustion markers, and increased cytotoxicity in vitro but decreased bone marrow infiltration in vivo. Patients treated with CAR T cell products enriched in CAR(High) T cells show significantly worse clinical response in several hematological malignancies.
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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