CAR density influences antitumoral efficacy of BCMA CAR T cells and correlates with clinical outcome
Authors/Creators
- Rodriguez-Marquez, Paula
- Calleja-Cervantes, Maria E
- Serrano, Guillermo
- Oliver-Caldes, Aina
- Palacios Barraquero, Maria L
- Martin-Mallo, Angel
- Calviño, Cristina
- Español-Rego, Marta
- Ceballos, Candela
- Lozano, Teresa
- Martin-Uriz, Patxi S
- 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, Ascensión
- San-Miguel, Jesús
- Fernández de Larrea, Carlos
- Hernaez, Mikel
- Rodriguez-Madoz, Juan R
- Prosper, Felipe
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 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.
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sciadv.abo0514.pdf
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