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

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

Object Details

• Location: Deutsche Nationalbibliothek Frankfurt am Main
• Extent: Online-Ressource
• Language: Englisch
• Notes: Nature communications. - 15 (2024) , 993, ISSN: 2041-1723

Contributors, Places and Time

• Event: Veröffentlichung
• (where): Freiburg
• (who): Universität
• (when): 2024
• Creator: 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, Stephanie ; 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

Further information

• DOI: 10.1038/s41467-024-45378-w
• URN: urn:nbn:de:bsz:25-freidok-2532849
• Rights: Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.
• Last update: 14.08.2025, 10:50 AM CEST