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

• Published in: Nature communications Vol. 15; no. 1; p. 993
• Main Authors: Märkl, Florian, Schultheiß, Christoph, Ali, Murtaza, Chen, Shih-Shih, Zintchenko, Marina, Egli, Lukas, Mietz, Juliane, Chijioke, Obinna, Paschold, Lisa, Spajic, Sebastijan, Holtermann, Anne, Dörr, Janina, Stock, Sophia, Zingg, Andreas, Läubli, Heinz, Piseddu, Ignazio, Anz, David, Minden, Marcus Dühren-von, Zhang, Tianjiao, Nerreter, Thomas, Hudecek, Michael, Minguet, Susana, Chiorazzi, Nicholas, Kobold, Sebastian, Binder, Mascha
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group 02.02.2024; Nature Portfolio
• Subjects: Animal models; B-cell receptor; Biocompatibility; Biomarkers; Cell therapy; Chimeric antigen receptors; Chronic lymphocytic leukemia; Cytolysis; Cytotoxicity; Epitopes; Leukemia; Lymphocytes; Lymphocytes B; Lymphocytes T; Lymphoma; Malignancy; Mutation; Point mutation; Receptors; Tumors; Xenotransplantation
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-45378-w

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 (IGLV3-21 R110 ) 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 IGLV3-21 R110 expressing cell lines and primary CLL cells, but neither cells expressing the non-pathogenic IGLV3-21 G110 light chain nor polyclonal healthy B cells. In vivo experiments confirm epitope-selective cytolysis in xenograft models in female mice using engrafted IGLV3-21 R110 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.