Severe hematotoxicity after CD19 CAR-T therapy is associated with suppressive immune dysregulation and limited CAR-T expansion
Kai Rejeski, Ariel Perez Perez, Gloria Iacoboni, Viktoria Blumenberg, Veit Bücklein, Simon Völkl, Olaf Penack, Omar Albanyan, Sophia Stock, Fabian Müller, Philipp Karschnia, Agnese Petrera, Kayla Reid, Rawan Faramand, Marco L. Davila, Karnav Modi, Erin Dean, Christina A. Bachmeier, Michael von Bergwelt‐Baildon, Frederick L. Locke, Wolfgang Bethge, Lars Bullinger, Andréas Mackensen, Pere Barba, Michael D. Jain, Marion Subklewe
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.