TY  - JOUR
AU  - Rejeski, Kai
AU  - Perez, Ariel
AU  - Iacoboni, Gloria
AU  - Blumenberg, Viktoria
AU  - Bücklein, Veit L
AU  - Völkl, Simon
AU  - Penack, Olaf
AU  - Albanyan, Omar
AU  - Stock, Sophia
AU  - Müller, Fabian
AU  - Karschnia, Philipp
AU  - Petrera, Agnese
AU  - Reid, Kayla
AU  - Faramand, Rawan
AU  - Davila, Marco L
AU  - Modi, Karnav
AU  - Dean, Erin A
AU  - Bachmeier, Christina
AU  - von Bergwelt-Baildon, Michael
AU  - Locke, Frederick L
AU  - Bethge, Wolfgang
AU  - Bullinger, Lars
AU  - Mackensen, Andreas
AU  - Barba, Pere
AU  - Jain, Michael D
AU  - Subklewe, Marion
TI  - Severe hematotoxicity after CD19 CAR-T therapy is associated with suppressive immune dysregulation and limited CAR-T expansion.
JO  - Science advances
VL  - 9
IS  - 38
SN  - 2375-2548
CY  - Washington, DC [u.a.]
PB  - Assoc.
M1  - DKFZ-2023-01923
SP  - eadg3919
PY  - 2023
AB  - 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.
KW  - Humans
KW  - Immunotherapy, Adoptive: adverse effects
KW  - Receptors, Chimeric Antigen
KW  - Adaptor Proteins, Signal Transducing
KW  - Antigens, CD19
KW  - Cell Cycle
KW  - Receptors, Chimeric Antigen (NLM Chemicals)
KW  - Adaptor Proteins, Signal Transducing (NLM Chemicals)
KW  - Antigens, CD19 (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:37738350
C2  - pmc:PMC10516499
DO  - DOI:10.1126/sciadv.adg3919
UR  - https://inrepo02.dkfz.de/record/283136
ER  -