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An anti-CD19/CTLA-4 switch improves efficacy and selectivity of CAR T cells targeting CD80/86-upregulated DLBCL

Chimeric antigen receptor T cell (CAR T) therapy is a potent treatment for relapsed/refractory (r/r) B cell lymphomas but provides lasting remissions in only ∼40% of patients and is associated with serious adverse events. We identify an upregulation of CD80 and/or CD86 in tumor tissue of (r/r) diffu...

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Main Authors: Prinz, Lars Fabian (Author) , Riet, Tobias (Author) , Neureuther, Daniel Felix (Author) , Lennartz, Simon (Author) , Chrobok, Danuta (Author) , Hübbe, Hanna (Author) , Uhl, Gregor (Author) , Riet, Nicole (Author) , Hofmann, Petra (Author) , Hösel, Marianna (Author) , Simon, Adrian Georg (Author) , Tetenborg, Luis (Author) , Segbers, Paul (Author) , Shimono, Joji (Author) , Gödel, Philipp (Author) , Balke-Want, Hyatt (Author) , Flümann, Ruth (Author) , Knittel, Gero (Author) , Reinhardt, Christian (Author) , Scheid, Christoph (Author) , Büttner, Reinhard (Author) , Chapuy, Björn (Author) , Ullrich, Roland (Author) , Hallek, Michael (Author) , Chmielewski, Markus Martin (Author)
Format: Article (Journal)
Language:English
Published: 20 February 2024
In: Cell reports. Medicine
Year: 2024, Volume: 5, Issue: 2, Pages: [1], 1-16, e1-e9
ISSN:2666-3791
DOI:10.1016/j.xcrm.2024.101421
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1016/j.xcrm.2024.101421
Verlag, kostenfrei, Volltext: https://www.sciencedirect.com/science/article/pii/S2666379124000442
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Author Notes:Lars Fabian Prinz, Tobias Riet, Daniel Felix Neureuther, Simon Lennartz, Danuta Chrobok, Hanna Hübbe, Gregor Uhl, Nicole Riet, Petra Hofmann, Marianna Hösel, Adrian Georg Simon, Luis Tetenborg, Paul Segbers, Joji Shimono, Philipp Gödel, Hyatt Balke-Want, Ruth Flümann, Gero Knittel, Hans Christian Reinhardt, Christoph Scheid, Reinhard Büttner, Björn Chapuy, Roland Tillmann Ullrich, Michael Hallek, and Markus Martin Chmielewski
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Summary:Chimeric antigen receptor T cell (CAR T) therapy is a potent treatment for relapsed/refractory (r/r) B cell lymphomas but provides lasting remissions in only ∼40% of patients and is associated with serious adverse events. We identify an upregulation of CD80 and/or CD86 in tumor tissue of (r/r) diffuse large B cell lymphoma (DLBCL) patients treated with tisagenlecleucel. This finding leads to the development of the CAR/CCR (chimeric checkpoint receptor) design, which consists of a CD19-specific first-generation CAR co-expressed with a recombinant CTLA-4-linked receptor with a 4-1BB co-stimulatory domain. CAR/CCR T cells demonstrate superior efficacy in xenograft mouse models compared with CAR T cells, superior long-term activity, and superior selectivity in in vitro assays with non-malignant CD19+ cells. In addition, immunocompetent mice show an intact CD80−CD19+ B cell population after CAR/CCR T cell treatment. The results reveal the CAR/CCR design as a promising strategy for further translational study.
Item Description:Online veröffentlicht: 9. Februar 2024, Artikelversion: 20. Februar 2024
Gesehen am 20.08.2024
Physical Description:Online Resource
ISSN:2666-3791
DOI:10.1016/j.xcrm.2024.101421

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