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Severe hematotoxicity after CD19 CAR-T therapy is associated with suppressive immune dysregulation and limited CAR-T expansion.

Marion SubkleweAriel PerezGloria IacoboniViktoria BlumenbergVeit L BückleinSimon VölklOlaf PenackOmar AlbanyanSophia StockFabian MüllerPhilipp KarschniaAgnese PetreraKayla M ReidRawan G FaramandMarco L DavilaKarnav ModiErin A DeanChristina A BachmeierMichael von Bergwelt-BaildonFrederick L LockeWolfgang Andreas BethgeLars BullingerAndreas MackensenPere BarbaMichael D JainMarion Subklewe
Published in: Science advances (2023)
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.
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