Im, Nam Gyu, Guillaumet-Adkins, Amy, Wal, Megha, Rogers, Anna J., Frede, Julia ORCID: 0000-0002-4380-9673, Havig, Claire C., Yang, Jing, Anand, Praveen ORCID: 0000-0002-2478-7042, Stegmann, Sarah K., Waldschmidt, Johannes M., Sotudeh, Noori, Niu, Leili, Voisine, Jordan ORCID: 0000-0002-8473-3759, Schweiger, Michal R., Grassberger, Clemens, Lohr, Jens G. and Knoechel, Birgit (2022). Regulatory Programs of B-cell Activation and Germinal Center Reaction Allow B-ALL Escape from CD19 CAR T-cell Therapy. Cancer Immunol. Res., 10 (9). S. 1055 - 1069. PHILADELPHIA: AMER ASSOC CANCER RESEARCH. ISSN 2326-6074

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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 CD19(low) 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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Im, Nam GyuUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Guillaumet-Adkins, AmyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wal, MeghaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rogers, Anna J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Frede, JuliaUNSPECIFIEDorcid.org/0000-0002-4380-9673UNSPECIFIED
Havig, Claire C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Yang, JingUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Anand, PraveenUNSPECIFIEDorcid.org/0000-0002-2478-7042UNSPECIFIED
Stegmann, Sarah K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Waldschmidt, Johannes M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sotudeh, NooriUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Niu, LeiliUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Voisine, JordanUNSPECIFIEDorcid.org/0000-0002-8473-3759UNSPECIFIED
Schweiger, Michal R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Grassberger, ClemensUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lohr, Jens G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Knoechel, BirgitUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-689003
DOI: 10.1158/2326-6066.CIR-21-0626
Journal or Publication Title: Cancer Immunol. Res.
Volume: 10
Number: 9
Page Range: S. 1055 - 1069
Date: 2022
Publisher: AMER ASSOC CANCER RESEARCH
Place of Publication: PHILADELPHIA
ISSN: 2326-6074
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
RNA-SEQ; ANTIGEN; IBRUTINIB; EFFICACY; DYNAMICS; RESISTANCE; REMISSION; RESPONSES; CHILDREN; BTKMultiple languages
Oncology; ImmunologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/68900

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