Severe hematotoxicity after CD19 CAR-T therapy is associated with suppressive immune dysregulation and limited CAR-T expansion
Rejeski, Kai (University Hospital (Munich, Alemanya))
Perez, Ariel (Miami Cancer Institute)
Iacoboni, Gloria (Universitat Autònoma de Barcelona. Departament de Medicina)
Blumenberg, Viktoria (University Hospital (Munich, Alemanya))
Bücklein, Veit (Bavarian Cancer Research Center (Alemnya))
Völkl, Simon (University Hospital Erlangen (Alemanya))
Penack, Olaf (Charité-Universitätsmedizin Berlin)
Albanyan, Omar (King Fahad Specialist Hospital (Dammam, Saudi Arabia))
Stock, Sophia (German Cancer Consortium (DKTK))
Müller, Fabian (Friedrich-Alexander-Universität Erlangen-Nürnberg)
Karschnia, Philipp (University Hospital (Munich, Alemanya))
Petrera, Agnese (Helmholtz Zentrum Munich)
Reid, Kayla (Moffitt Cancer Center (Tampa, Estats Units d'Amèrica))
Faramand, Rawan (Moffitt Cancer Center (Tampa, Estats Units d'Amèrica))
Davila, Marco L. (Moffitt Cancer Center (Tampa, Estats Units d'Amèrica))
Modi, Karnav (Moffitt Cancer Center (Tampa, Estats Units d'Amèrica))
Dean, Erin A. (University of Florida)
Bachmeier, Christina (Moffitt Cancer Center (Tampa, Estats Units d'Amèrica))
von Bergwelt-Baildon, Michael (Bavarian Cancer Research Center (Alemanya))
Locke, Frederick L (Moffitt Cancer Center (Tampa, Estats Units d'Amèrica))
Bethge, Wolfgang (University Hospital of Tübingen (Alemanya))
Bullinger, Lars (Humboldt-Universität zu Berlin)
Mackensen, Andreas (Friedrich-Alexander-Universität Erlangen-Nürnberg)
Barba, Pere (Universitat Autònoma de Barcelona. Departament de Medicina)
Jain, Michael D. (Moffitt Cancer Center (Tampa, Estats Units d'Amèrica))
Subklewe, Marion (Bavarian Cancer Research Center (Alemanya))

Date:	2023
Abstract:	Prolonged cytopenias after chimeric antigen receptor (CAR) T cell therapy are a significant clinical problem and the underlying pathophysiology remains poorly understood. Here, we investigated how (CAR) T cell expansion dynamics and serum proteomics affect neutrophil recovery phenotypes after CD19-directed CAR T cell therapy. Survival favored patients with "intermittent" neutrophil recovery (e. g. , recurrent neutrophil dips) compared to either "quick" or "aplastic" recovery. While intermittent patients displayed increased CAR T cell expansion, aplastic patients exhibited an unfavorable relationship between expansion and tumor burden. Proteomics of patient serum collected at baseline and in the first month after CAR-T therapy revealed higher markers of endothelial dysfunction, inflammatory cytokines, macrophage activation, and T cell suppression in the aplastic phenotype group. Prolonged neutrophil aplasia thus occurs in patients with systemic immune dysregulation at baseline with subsequently impaired CAR-T expansion and myeloid-related inflammatory changes. The association between neutrophil recovery and survival outcomes highlights critical interactions between host hematopoiesis and the immune state stimulated by CAR-T infusion. Post CAR-T neutrophil recovery phenotypes impact survival and reflect CAR expansion kinetics and serum proteomic changes.
Note:	Altres ajuts: Ludwig-Maximilians-Universität München INST 409/225-1 FUGG
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Published in:	Science advances, Vol. 9 (september 2023) , ISSN 2375-2548

DOI: 10.1126/sciadv.adg3919
PMID: 37738350

16 p, 3.3 MB

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