Mutation-specific CAR T cells as precision therapy for IGLV3-21R110 expressing high-risk chronic lymphocytic leukemia
Maerkl, F.; Schultheiss, C.; Ali, M.; Chen, S.-S.; Egli, L.; Mietz, J.; Chijoke, O.; Paschold, L.; Spajic, S.; Holtermann, A.; Doerr, J.; Stock, S.; Piseddu, I.; Anz, D.; Duehren-von Minden, M.; Zhang, T.; Nerreter, T.; Hudecek, M.; Chiorazzi, N.; Kobold, S.; Binder, M.
Show 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 used 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 developed murine and humanized CAR constructs expressed in T cells from healthy donors and CLL patients that eradicated IGLV3-21R110 expressing cell lines and primary CLL cells, but not polyclonal healthy B cells. In vivo experiments confirmed epitope-selective cytolysis in xenograft models 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 novel avenues of resistance-preventive and biomarker-guided cellular targeting of functionally relevant lymphoma driver mutations sparing normal B cells.
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