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

Florian Märkl, Christoph Schultheiß, Murtaza Ali, Shih-Shih Chen, Marina Zintchenko, Lukas Egli, Juliane Mietz, Obinna Chijioke, Lisa Paschold, Sebastijan Spajic, Anne Holtermann, Janina Dörr, Sophia Stock, Andreas Zingg, Heinz Läubli, Ignazio Piseddu, David Anz, Marcus Dühren- von Minden, Tianjiao Zhang, Thomas Nerreter, Michael Hudecek, Susana Minguet, Nicholas Chiorazzi, Sebastian Kobold () and Mascha Binder ()
Additional contact information
Florian Märkl: Klinikum der Universität München
Christoph Schultheiß: University Hospital Basel
Murtaza Ali: Martin-Luther-University Halle-Wittenberg
Shih-Shih Chen: Northwell Health
Marina Zintchenko: University of Freiburg
Lukas Egli: University of Zurich
Juliane Mietz: University of Zurich
Obinna Chijioke: University of Zurich
Lisa Paschold: Martin-Luther-University Halle-Wittenberg
Sebastijan Spajic: Klinikum der Universität München
Anne Holtermann: Klinikum der Universität München
Janina Dörr: Klinikum der Universität München
Sophia Stock: Klinikum der Universität München
Andreas Zingg: University Hospital Basel
Heinz Läubli: University Hospital Basel
Ignazio Piseddu: Klinikum der Universität München
David Anz: Klinikum der Universität München
Marcus Dühren- von Minden: AVA-lifescience GmbH
Tianjiao Zhang: Martin-Luther-University Halle-Wittenberg
Thomas Nerreter: Medizinische Klinik und Poliklinik II, Universitätsklinikum Würzburg
Michael Hudecek: Medizinische Klinik und Poliklinik II, Universitätsklinikum Würzburg
Susana Minguet: University of Freiburg
Nicholas Chiorazzi: Northwell Health
Sebastian Kobold: Klinikum der Universität München
Mascha Binder: University Hospital Basel

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-45378-w

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