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, Mascha Binder
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 (IGLV3-21 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.