1. Mutation-specific CAR T cells as precision therapy for IGLV3-21R110 expressing high-risk chronic lymphocytic leukemia
- Author
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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
- Subjects
Science - 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.
- Published
- 2024
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