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

Autor:	Prinz LF; Department I of Internal Medicine, University Hospital Cologne, 50937 Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), 50931 Cologne, Germany. Electronic address: lars.prinz1@uk-koeln.de., Riet T; Department I of Internal Medicine, University Hospital Cologne, 50937 Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), 50931 Cologne, Germany., Neureuther DF; Department I of Internal Medicine, University Hospital Cologne, 50937 Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), 50931 Cologne, Germany., Lennartz S; Department I of Internal Medicine, University Hospital Cologne, 50937 Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), 50931 Cologne, Germany., Chrobok D; Department I of Internal Medicine, University Hospital Cologne, 50937 Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), 50931 Cologne, Germany., Hübbe H; Heidelberg University, 69117 Heidelberg, Germany., Uhl G; Department I of Internal Medicine, University Hospital Cologne, 50937 Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), 50931 Cologne, Germany., Riet N; Center for Molecular Medicine Cologne (CMMC), 50931 Cologne, Germany., Hofmann P; Department I of Internal Medicine, University Hospital Cologne, 50937 Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), 50931 Cologne, Germany., Hösel M; Department I of Internal Medicine, University Hospital Cologne, 50937 Cologne, Germany., Simon AG; Institute of Pathology, University Hospital Cologne, 50937 Cologne, Germany., Tetenborg L; Department I of Internal Medicine, University Hospital Cologne, 50937 Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), 50931 Cologne, Germany., Segbers P; Department I of Internal Medicine, University Hospital Cologne, 50937 Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), 50931 Cologne, Germany., Shimono J; Department of Hematology, Oncology and Tumorimmunology, Charité University Medical Center Berlin, Benjamin Franklin Campus, 12203 Berlin, Germany., Gödel P; Department I of Internal Medicine, University Hospital Cologne, 50937 Cologne, Germany., Balke-Want H; Department I of Internal Medicine, University Hospital Cologne, 50937 Cologne, Germany; Stanford Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University, Stanford, CA, USA., Flümann R; Department I of Internal Medicine, University Hospital Cologne, 50937 Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), 50931 Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany; Mildred Scheel School of Oncology Aachen Bonn Cologne Düsseldorf (MSSO ABCD), Faculty of Medicine and University Hospital of Cologne, Cologne, Germany; Max Planck Institute for Biology of Ageing, Joseph-Stelzmann-Str. 9b, 50931 Cologne, Germany; University Hospital Essen, Department of Hematology and Stem Cell Transplantation, West German Cancer Center, German Cancer Consortium Partner Site Essen, Center for Molecular Biotechnology, Hufelandstr. 55, 45147 Essen, Germany., Knittel G; University Hospital Essen, Department of Hematology and Stem Cell Transplantation, West German Cancer Center, German Cancer Consortium Partner Site Essen, Center for Molecular Biotechnology, Hufelandstr. 55, 45147 Essen, Germany., Reinhardt HC; University Hospital Essen, Department of Hematology and Stem Cell Transplantation, West German Cancer Center, German Cancer Consortium Partner Site Essen, Center for Molecular Biotechnology, Hufelandstr. 55, 45147 Essen, Germany., Scheid C; Department I of Internal Medicine, University Hospital Cologne, 50937 Cologne, Germany., Büttner R; Institute of Pathology, University Hospital Cologne, 50937 Cologne, Germany., Chapuy B; Department of Hematology, Oncology and Tumorimmunology, Charité University Medical Center Berlin, Benjamin Franklin Campus, 12203 Berlin, Germany., Ullrich RT; Department I of Internal Medicine, University Hospital Cologne, 50937 Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), 50931 Cologne, Germany., Hallek M; Department I of Internal Medicine, University Hospital Cologne, 50937 Cologne, Germany., Chmielewski MM; Department I of Internal Medicine, University Hospital Cologne, 50937 Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), 50931 Cologne, Germany. Electronic address: markus.chmielewski@uk-koeln.de.
Jazyk:	angličtina
Zdroj:	Cell reports. Medicine [Cell Rep Med] 2024 Feb 20; Vol. 5 (2), pp. 101421. Date of Electronic Publication: 2024 Feb 09.
DOI:	10.1016/j.xcrm.2024.101421
Abstrakt:	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. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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