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However, the treatment fails in 50% of patients, often due to CD19 antigen loss. Alternative immunotherapies targeting other antigens are being tested but show limited efficacy, especially in cases of lineage switching or loss of B-cell phenotype, highlighting the need for novel targets. Herein, we identified leukocyte-immunoglobulin-like-receptor-B1 (LILRB1, CD85j) as a novel target for CAR-T cells through cell surface proteomics on patient-derived samples of high-risk B-cell acute lymphoblastic leukemia (B-ALL). LILRB1, an immune inhibitory receptor, is normally expressed only on monocytes and B-cells. We observed stable LILRB1 expression in B-ALL and B-cell non-Hodgkin lymphoma (B-NHL), even after CD20\/CD19-based immunotherapies. LILRB1 CAR-T cells showed antigen-specific antitumor activity in vitro against B-ALL\/B-NHL cells, including those resistant to CD19 CAR-T-cells, and in vivo in B-ALL xenografts. Additionally, we identified LILRB1 in monocytic acute myeloid leukemia (AML) and demonstrated LILRB1 CAR-T cell cytotoxicity against AML cell lines in vitro and in vivo. These findings establish LILRB1 as a novel target for cancer immunotherapy and show evidence for the preclinical efficacy of LILRB1 CAR-T cells against haematological malignancies, including cases resistant to previous lines of immunotherapy, thus holding promise for further clinical development.<\/jats:p>","DOI":"10.1038\/s41375-025-02580-z","type":"journal-article","created":{"date-parts":[[2025,4,4]],"date-time":"2025-04-04T23:53:20Z","timestamp":1743810800000},"page":"1395-1411","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["LILRB1-directed CAR-T cells for the treatment of hematological malignancies"],"prefix":"10.1038","volume":"39","author":[{"given":"Katsiaryna","family":"Marhelava","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Klaudyna","family":"Fidyt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3506-8040","authenticated-orcid":false,"given":"Monika","family":"Pepek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9487-1744","authenticated-orcid":false,"given":"Marta","family":"Krawczyk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Forcados","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agata","family":"Malinowska","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bianka","family":"Swiderska","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6421-1080","authenticated-orcid":false,"given":"Narcis","family":"Fernandez-Fuentes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalia","family":"Czerwik","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iwona","family":"Baranowska","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7647-3336","authenticated-orcid":false,"given":"Agnieszka","family":"Krzywdzinska","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lukasz","family":"Sedek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lukasz","family":"Slota","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bartosz","family":"Perkowski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alicia","family":"Villatoro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thibault","family":"Leray","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ewa","family":"Lech-Maranda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pablo","family":"Menendez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Else Marit","family":"Inderberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S\u00e9bastien","family":"W\u00e4lchli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magdalena","family":"Winiarska","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1719-5233","authenticated-orcid":false,"given":"Malgorzata","family":"Firczuk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,4,5]]},"reference":[{"key":"2580_CR1","doi-asserted-by":"publisher","first-page":"439","DOI":"10.1056\/NEJMoa1709866","volume":"378","author":"SL Maude","year":"2018","unstructured":"Maude SL, Laetsch TW, Buechner J, Rives S, Boyer M, Bittencourt H, et al. 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