{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,13]],"date-time":"2026-11-13T03:35:00Z","timestamp":1794540900918,"version":"4.9.1"},"reference-count":54,"publisher":"American Society of Hematology","issue":"2","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2026,1,8]]},"abstract":"<jats:sec>\n                    <jats:title>Abstract<\/jats:title>\n                    <jats:p>Current therapies, including autologous chimeric antigen receptor (CAR) T-cell immunotherapy, fail to cure half of infants with KMT2A-rearranged acute lymphoblastic leukemia (KMT2Ar-ALL), a disease characterized by frequent central nervous system involvement, poor treatment response, early relapse, and lineage switching. More effective treatment strategies, including the availability of off-the-shelf immunotherapies, is particularly relevant in infants. PROM1\/CD133 is a direct target of KMT2A-fusion oncoproteins and is expressed on leukemic cells. Allogeneic invariant natural killer T (iNKT) cells, \u201cinnately\u201d more powerful effectors than T cells, can be deployed off-the-shelf without risk of acute graft-versus-host disease. Here, we equip iNKT cells with CD19- and\/or CD133-targeting CARs, and investigate their antileukemia activity against KMT2Ar-ALL in relevant in vitro and in vivo models. Compared with monospecific counterparts and dual, bispecific CAR T cells, bispecific CD19-CD133 CAR-iNKT cells have a more potent antileukemia activity, effectively targeting both CAR antigen\u2013high and \u2013low leukemia. Bispecific CAR-iNKT cells eradicate medullary and, notably, leptomeningeal leukemia, and induce sustained remissions without discernible hematologic toxicity. Mechanistically, the more potent antileukemia effect of CAR-iNKT cells over CAR T cells is mediated by a pronounced CAR-dependent and CAR antigen\u2013dependent upregulation of the innate activating receptor NKG2D on CAR-iNKT cells, and its engagement by its corresponding ligands on KMT2Ar-ALL cells. This ensures effective leukemia targeting even with downregulation of CD133 or CD19. Thus, by engaging with 2 different types of leukemia-associated antigens, that is, CAR antigens and NKG2D ligands, CAR-iNKT cells provide a powerful platform for the treatment of KMT2Ar-ALL. This approach can be readily adapted for other high-risk malignancies, including those with otherwise difficult to target leptomeningeal involvement.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1182\/blood.2025029302","type":"journal-article","created":{"date-parts":[[2025,9,3]],"date-time":"2025-09-03T07:52:07Z","timestamp":1756885927000},"page":"180-196","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":14,"title":["Off-the-shelf dual CAR-iNKT cell immunotherapy eradicates medullary and leptomeningeal high-risk\n                    <i>KMT2A<\/i>\n                    -rearranged leukemia"],"prefix":"10.1182","volume":"147","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7060-3753","authenticated-orcid":false,"given":"Hongwei","family":"Ren","sequence":"first","affiliation":[{"name":"1Centre for Haematology, Department of Immunology and Inflammation, Imperial College London, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6713-7349","authenticated-orcid":false,"given":"Natalina","family":"Elliott","sequence":"additional","affiliation":[{"name":"2Department of Paediatrics, University of Oxford, Oxford, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5058-7469","authenticated-orcid":false,"given":"Bryan","family":"Lye","sequence":"additional","affiliation":[{"name":"1Centre for Haematology, Department of Immunology and Inflammation, Imperial College London, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammad Umer","family":"Sharif Shohan","sequence":"additional","affiliation":[{"name":"3Department of Biochemistry, University of Oxford, Oxford, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joe W.","family":"Cross","sequence":"additional","affiliation":[{"name":"2Department of Paediatrics, University of Oxford, Oxford, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucy","family":"Field","sequence":"additional","affiliation":[{"name":"2Department of Paediatrics, University of Oxford, Oxford, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kanagaraju","family":"Ponnusamy","sequence":"additional","affiliation":[{"name":"1Centre for Haematology, Department of Immunology and Inflammation, Imperial College London, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siobhan","family":"Rice","sequence":"additional","affiliation":[{"name":"4MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United 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Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7636-1599","authenticated-orcid":false,"given":"Jonathan","family":"Bond","sequence":"additional","affiliation":[{"name":"7National Children's Cancer Service, Children's Health Ireland at Crumlin, Dublin, Ireland"},{"name":"8Systems Biology Ireland, School of Medicine, University College Dublin, Dublin, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6094-6397","authenticated-orcid":false,"given":"Irene A. G.","family":"Roberts","sequence":"additional","affiliation":[{"name":"2Department of Paediatrics, University of Oxford, Oxford, United Kingdom"},{"name":"4MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5449-5246","authenticated-orcid":false,"given":"Christina","family":"Halsey","sequence":"additional","affiliation":[{"name":"9Wolfson Wohl Cancer Research Centre, College of Medical Veterinary and Life Sciences, School of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachael","family":"Bashford-Rogers","sequence":"additional","affiliation":[{"name":"3Department of Biochemistry, University of Oxford, Oxford, United Kingdom"},{"name":"10Cancer Research UK Oxford Centre, University of Oxford, Oxford, United 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