Publicaciones científicas
Molecular mechanisms promoting long-term cytopenia after BCMA CAR-T therapy in Multiple Myeloma
Maria Luisa Palacios-Berraquero 1, Paula Rodriguez-Marquez 2, Maria Erendira Calleja-Cervantes 2, Nerea Berastegui 3, Aintzane Zabaleta 4, Leire Burgos 5, Diego Alignani 6, Patxi San Martín-Úriz 7, Amaia Vilas-Zornoza 8, Saray Rodriguez-Diaz 2, Susana I Inoges 9, Ascensión López-Diaz-de-Cerio 10, Sofia Huerga 11, Luis Esteban Tamariz-Amador 12, Jose J Rifon 13, Ana Alfonso-Pierola 13, Juan Jose Lasarte 14, Bruno Paiva 15, Mikel Hernaez 3, Paula Rodriguez-Otero 16, Jesús F San-Miguel 17, Teresa Ezponda 7, Juan Roberto Rodriguez-Madoz 2, Felipe Prosper 18
Abstract
Hematological toxicity is a common side effect of CAR-T therapies, particularly severe in relapsed/refractory multiple myeloma (MM) patients. In this study, we analyzed a cohort of 48 patients treated with BCMA CAR-T cells to characterize the kinetics of cytopenia, identify predictive factors and determine potential mechanism underlying these toxicities.
The overall incidence of cytopenia was 95.7%, and grade>3 thrombocytopenia and neutropenia, one month after infusion, was observed in 57% and 53% of the patients, being still present after one year in 4 and 3 patients respectively. Presence of cytopenia at baseline and high peak inflammatory markers highly correlated with cytopenia persisting up to three months. To determine potential mechanisms underpinning cytopenias, we evaluated the paracrine effect of BCMA CAR-T cells on HSPCs differentiation using an ex-vivo myeloid differentiation model. Phenotypic analysis showed that supernatants from activated CAR-T cells (spCAR) halted HSPCs differentiation, promoting more immature phenotypes, with reduced expression of granulocytic, monocytic and erythroid markers, which could be prevented with a combination of IFNγ, TNFα/β, TGFβ, IL-6 and IL-17 inhibitors.
Single-cell RNA-seq demonstrated upregulation of transcription factors associated with early stages of hematopoietic differentiation in the presence of spCAR (GATA2, RUNX1, CEBPA) and decreased activity of key regulons involved in neutrophil and monocytic maturation (ID2, MAFB). Our results suggest that CAR-T cell activation negatively influences hematopoietic differentiation through paracrine effects inducing HSPCs maturation arrest. Moreover, our study contributes to the understanding of severe cytopenia observed after CAR-T therapy in MM and provides potential treatments to prevent or decrease its severity.
CITA DEL ARTÍCULO Blood Adv. 2024 Jul 26:bloodadvances.2023012522. doi: 10.1182/bloodadvances.2023012522. Online ahead of print.
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