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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<jats:sup>R110<\/jats:sup>) 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<jats:sup>R110<\/jats:sup> expressing cell lines and primary CLL cells, but neither cells expressing the non-pathogenic IGLV3-21<jats:sup>G110<\/jats:sup> light chain nor polyclonal healthy B cells. In vivo experiments confirm epitope-selective cytolysis in xenograft models in female mice using engrafted IGLV3-21<jats:sup>R110<\/jats:sup> 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.<\/jats:p>","DOI":"10.1038\/s41467-024-45378-w","type":"journal-article","created":{"date-parts":[[2024,2,2]],"date-time":"2024-02-02T11:02:05Z","timestamp":1706871725000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Mutation-specific CAR T cells as precision therapy for IGLV3-21R110 expressing high-risk chronic lymphocytic leukemia"],"prefix":"10.1038","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4285-0380","authenticated-orcid":false,"given":"Florian","family":"M\u00e4rkl","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9789-5776","authenticated-orcid":false,"given":"Christoph","family":"Schulthei\u00df","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Murtaza","family":"Ali","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shih-Shih","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"Zintchenko","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lukas","family":"Egli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-9359-2242","authenticated-orcid":false,"given":"Juliane","family":"Mietz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4247-5947","authenticated-orcid":false,"given":"Obinna","family":"Chijioke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0020-1315","authenticated-orcid":false,"given":"Lisa","family":"Paschold","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastijan","family":"Spajic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Holtermann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9447-882X","authenticated-orcid":false,"given":"Janina","family":"D\u00f6rr","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophia","family":"Stock","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Zingg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8910-5620","authenticated-orcid":false,"given":"Heinz","family":"L\u00e4ubli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ignazio","family":"Piseddu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Anz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcus 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The use of the afore mentioned antibody sequences in CAR T cells is subject to the current patent application EP22186810.2 by M.D.M. and M.B. S.K., M.H. and T.N. are inventors of several patents in the field of cellular therapies. S.K. has received honoraria from BMS, GSK, Galapagos, Cymab, Novartis, Miltenyi Biomedicines and TCR2 Inc. S.K. has received license payments from TCR2 Inc and Carina Biotech. S.K. received research support from Arcus Biosciences, Plectonic GmbH, Tabby Therapeutics, Catalym GmbH and TCR2 Inc for work unrelated to this manuscript. All other authors disclose no potential conflicts of interest.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"993"}}