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Supplementary Data from Regulatory Programs of B-cell Activation and Germinal Center Reaction Allow B-ALL Escape from CD19 CAR T-cell Therapy

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posted on 2023-04-04, 01:44 authored by Nam Gyu Im, Amy Guillaumet-Adkins, Megha Wal, Anna J. Rogers, Julia Frede, Claire C. Havig, Jing Yang, Praveen Anand, Sarah K. Stegmann, Johannes M. Waldschmidt, Noori Sotudeh, Leili Niu, Jordan Voisine, Michal R. Schweiger, Clemens Grassberger, Jens G. Lohr, Birgit Knoechel
Supplementary Data from Regulatory Programs of B-cell Activation and Germinal Center Reaction Allow B-ALL Escape from CD19 CAR T-cell Therapy

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ARTICLE ABSTRACT

Chimeric antigen receptor (CAR) T-cell therapy has led to tremendous successes in the treatment of B-cell malignancies. However, a large fraction of treated patients relapse, often with disease expressing reduced levels of the target antigen. Here, we report that exposing CD19+ B-cell acute lymphoblastic leukemia (B-ALL) cells to CD19 CAR T cells reduced CD19 expression within hours. Initially, CD19 CAR T cells caused clustering of CD19 at the T cell–leukemia cell interface followed by CD19 internalization and decreased CD19 surface expression on the B-ALL cells. CD19 expression was then repressed by transcriptional rewiring. Using single-cell RNA sequencing and single-cell assay for transposase-accessible chromatin using sequencing, we demonstrated that a subset of refractory CD19low cells sustained decreased CD19 expression through transcriptional programs of physiologic B-cell activation and germinal center reaction. Inhibiting B-cell activation programs with the Bruton's tyrosine kinase inhibitor ibrutinib increased the cytotoxicity of CD19 CAR T cells without affecting CAR T-cell viability. These results demonstrate transcriptional plasticity as an underlying mechanism of escape from CAR T cells and highlight the importance of combining CAR T-cell therapy with targeted therapies that aim to overcome this plasticity.See related Spotlight by Zhao and Melenhorst, p. 1040

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    Cancer Immunology Research

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