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Märkl, F.* ; Schultheiß, C.* ; Ali, M.* ; Chen, S.S.* ; Zintchenko, M.* ; Egli, L.* ; Mietz, J.* ; Chijioke, O.* ; Paschold, L.* ; Spajic, S.* ; Holtermann, A.* ; Dörr, J.* ; Stock, S.* ; Zingg, A.* ; Läubli, H.* ; Piseddu, I.* ; Anz, D.* ; Minden, M.D.* ; Zhang, T.* ; Nerreter, T.* ; Hudecek, M.* ; Minguet, S.* ; Chiorazzi, N.* ; Kobold, S. ; Binder, M.*

Mutation-specific CAR T cells as precision therapy for IGLV3-21R110 expressing high-risk chronic lymphocytic leukemia.

Nat. Commun. 15:993 (2024)
Publ. Version/Full Text DOI PMC
Open Access Gold
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The concept of precision cell therapy targeting tumor-specific mutations is appealing but requires surface-exposed neoepitopes, which is a rarity in cancer. B cell receptors (BCR) of mature lymphoid malignancies are exceptional in that they harbor tumor-specific-stereotyped sequences in the form of point mutations that drive self-engagement of the BCR and autologous signaling. Here, we use a BCR light chain neoepitope defined by a characteristic point mutation (IGLV3-21R110) for selective targeting of a poor-risk subset of chronic lymphocytic leukemia (CLL) with chimeric antigen receptor (CAR) T cells. We develop murine and humanized CAR constructs expressed in T cells from healthy donors and CLL patients that eradicate IGLV3-21R110 expressing cell lines and primary CLL cells, but neither cells expressing the non-pathogenic IGLV3-21G110 light chain nor polyclonal healthy B cells. In vivo experiments confirm epitope-selective cytolysis in xenograft models in female mice using engrafted IGLV3-21R110 expressing cell lines or primary CLL cells. We further demonstrate in two humanized mouse models lack of cytotoxicity towards human B cells. These data provide the basis for advanced approaches of resistance-preventive and biomarker-guided cellular targeting of functionally relevant lymphoma driver mutations sparing normal B cells.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Chimeric Antigen Receptors; Xenograft Models; Light-chains; Immunoglobulin; Cll; Immunotherapy; Remissions; Transgene; Vectors; Driven
Language english
Publication Year 2024
HGF-reported in Year 2024
ISSN (print) / ISBN 2041-1723
e-ISSN 2041-1723
Journal Nature Communications
Quellenangaben Volume: 15, Issue: 1, Pages: , Article Number: 993 Supplement: ,
Publisher Nature Publishing Group
Publishing Place London
Reviewing status Peer reviewed
Institute(s) Unit for Clinical Pharmacology (KKG-EKLiP)
POF-Topic(s) 30203 - Molecular Targets and Therapies
Research field(s) Immune Response and Infection
PSP Element(s) G-522100-001
Grants Fritz-Bender-Stiftung
SFB-TRR 338/1
Monika-Kutzner-Stiftung
Deutsche Jose Carreras Leukamie-Stiftung
Wilhelm-Sander-Stiftung
Else-Kroner-Fresenius-Stiftung (IOLIN)
German Cancer Aid (AvantCAR.de)
Marie-Sklodowska-Curie Program Training Network for Optimizing Adoptive T Cell Therapy of Cancer - H2020 Program of the European Union
Melanoma Research Alliance Grants
International Doctoral Program iTarget: Immunotargeting of Cancer - Elite Network of Bavaria
Intramural Roux program funding
DFG
LMU Munich's Institutional Strategy LMUexcellent

Bruno und Helene Joster Foundation
European Research Council
Bavarian Research Foundation (BAYCELLATOR)
Bundesministerium fur Bildung und Forschung Projects Oncoattract, CONTRACT and Beyondantibody
FOR2799
Deutsche Forschungsgemeinschaft (DFG)
DOI 10.1038/s41467-024-45378-w
WOS ID 001156587200019
Scopus ID 85183827196
PubMed ID 38307904
Erfassungsdatum 2024-02-06
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