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Sequential antigen loss and branching evolution in lymphoma after CD19- and CD20-targeted T-cell-redirecting therapy

CD19 chimeric antigen receptor (CAR) T cells and CD20 targeting T-cell-engaging bispecific antibodies (bispecs) have been approved in B-cell non-Hodgkin lymphoma lately, heralding a new clinical setting in which patients are treated with both approaches, sequentially. The aim of our study was to inv...

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Main Authors: Duell, Johannes (Author) , Leipold, Alexander M. (Author) , Appenzeller, Silke (Author) , Fuhr, Viktoria (Author) , Rauert-Wunderlich, Hilka (Author) , Da Via, Matteo (Author) , Dietrich, Oliver (Author) , Toussaint, Christophe (Author) , Imdahl, Fabian (Author) , Eisele, Florian (Author) , Afrin, Nazia (Author) , Grundheber, Lars (Author) , Einsele, Hermann (Author) , Weinhold, Niels (Author) , Rosenwald, Andreas (Author) , Topp, Max S. (Author) , Saliba, Antoine-Emmanuel (Author) , Rasche, Leo (Author)
Format: Article (Journal)
Language:English
Published: 22 February 2024
In: Blood
Year: 2024, Volume: 143, Issue: 8, Pages: 685-696
ISSN:1528-0020
DOI:10.1182/blood.2023021672
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1182/blood.2023021672
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Author Notes:Johannes Duell, Alexander M. Leipold, Silke Appenzeller, Viktoria Fuhr, Hilka Rauert-Wunderlich, Matteo Da Via, Oliver Dietrich, Christophe Toussaint, Fabian Imdahl, Florian Eisele, Nazia Afrin, Lars Grundheber, Hermann Einsele, Niels Weinhold, Andreas Rosenwald, Max S. Topp, Antoine-Emmanuel Saliba, and Leo Rasche
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Summary:CD19 chimeric antigen receptor (CAR) T cells and CD20 targeting T-cell-engaging bispecific antibodies (bispecs) have been approved in B-cell non-Hodgkin lymphoma lately, heralding a new clinical setting in which patients are treated with both approaches, sequentially. The aim of our study was to investigate the selective pressure of CD19- and CD20-directed therapy on the clonal architecture in lymphoma. Using a broad analytical pipeline on 28 longitudinally collected specimen from 7 patients, we identified truncating mutations in the gene encoding CD20 conferring antigen loss in 80% of patients relapsing from CD20 bispecs. Pronounced T-cell exhaustion was identified in cases with progressive disease and retained CD20 expression. We also confirmed CD19 loss after CAR T-cell therapy and reported the case of sequential CD19 and CD20 loss. We observed branching evolution with re-emergence of CD20+ subclones at later time points and spatial heterogeneity for CD20 expression in response to targeted therapy. Our results highlight immunotherapy as not only an evolutionary bottleneck selecting for antigen loss variants but also complex evolutionary pathways underlying disease progression from these novel therapies.
Item Description:Online verfügbar 21 November 2023, Version des Artikels 22 February 2024
Gesehen am 25.09.2024
Physical Description:Online Resource
ISSN:1528-0020
DOI:10.1182/blood.2023021672

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