2f:I[703058,["/_next/static/immutable/chunks/3bhq_5eh1d760.js","/_next/static/immutable/chunks/1855-ogyi8eh4.js","/_next/static/immutable/chunks/2pfsjpn6k6zlg.js","/_next/static/immutable/chunks/26c7v3_3uwnwu.js","/_next/static/immutable/chunks/25a3ozcrvi1ff.js","/_next/static/immutable/chunks/2r4wx50nvjh_4.js","/_next/static/immutable/chunks/23fsw06hsi5b1.js","/_next/static/immutable/chunks/06_yt270h41rg.js","/_next/static/immutable/chunks/3ezsiz-7shkna.js","/_next/static/immutable/chunks/20x2y96ldu5wx.js","/_next/static/immutable/chunks/2lxntcm3pd1_h.js","/_next/static/immutable/chunks/00dgco8irq3jw.js","/_next/static/immutable/chunks/00nwe-kq0rboc.js","/_next/static/immutable/chunks/2051ffx3xzio9.js"],"PaperListPageClient"] 30:T7d1,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, "innately" 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-high and -low 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-dependent 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.31:T85f, Abstract 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, “innately” 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–high and –low 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–dependent 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. 25:[[["$","script","0",{"type":"application/ld+json","dangerouslySetInnerHTML":{"__html":"{\"@context\":\"https://schema.org\",\"@type\":\"CollectionPage\",\"name\":\"CAR-iNKT Cell Therapy: modality Research & Clinical Takeaways\",\"description\":\"Explore peer-reviewed papers on CAR-iNKT Cell Therapy (modality). Clinician-written summaries and actionable practice insights. 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leukemia"],"author":[{"given":"Hongwei","family":"Ren","sequence":"first","affiliation":[{"name":"1Centre for Haematology, Department of Immunology and Inflammation, Imperial College London, London, United Kingdom"}]},{"given":"Natalina","family":"Elliott","sequence":"additional","affiliation":[{"name":"2Department of Paediatrics, University of Oxford, Oxford, United Kingdom"}]},{"given":"Bryan","family":"Lye","sequence":"additional","affiliation":[{"name":"1Centre for Haematology, Department of Immunology and Inflammation, Imperial College London, London, United Kingdom"}]},{"given":"Mohammad Umer","family":"Sharif Shohan","sequence":"additional","affiliation":[{"name":"3Department of Biochemistry, University of Oxford, Oxford, United Kingdom"}]},{"given":"Joe W.","family":"Cross","sequence":"additional","affiliation":[{"name":"2Department of Paediatrics, University of Oxford, Oxford, United Kingdom"}]},{"given":"Lucy","family":"Field","sequence":"additional","affiliation":[{"name":"2Department of Paediatrics, University of Oxford, Oxford, United Kingdom"}]},{"given":"Kanagaraju","family":"Ponnusamy","sequence":"additional","affiliation":[{"name":"1Centre for Haematology, Department of Immunology and Inflammation, Imperial College London, London, United Kingdom"}]},{"given":"Siobhan","family":"Rice","sequence":"additional","affiliation":[{"name":"4MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom"}]},{"given":"Thomas","family":"Jackson","sequence":"additional","affiliation":[{"name":"2Department of Paediatrics, University of Oxford, Oxford, United Kingdom"}]},{"given":"Ilia","family":"Leontari","sequence":"additional","affiliation":[{"name":"1Centre for Haematology, Department of Immunology and Inflammation, Imperial College London, London, United Kingdom"}]},{"given":"Nouhad","family":"El Ouazzani","sequence":"additional","affiliation":[{"name":"5Department of Haematology, Great Ormond Street Hospital, London, United Kingdom"}]},{"given":"Rebecca","family":"Thomas","sequence":"additional","affiliation":[{"name":"5Department of Haematology, Great Ormond Street Hospital, London, United Kingdom"}]},{"given":"Sarah","family":"Inglott","sequence":"additional","affiliation":[{"name":"2Department of Paediatrics, University of Oxford, Oxford, United Kingdom"},{"name":"5Department of Haematology, Great Ormond Street Hospital, London, United Kingdom"}]},{"given":"Jack","family":"Bartram","sequence":"additional","affiliation":[{"name":"5Department of Haematology, Great Ormond Street Hospital, London, United Kingdom"}]},{"given":"Owen","family":"Smith","sequence":"additional","affiliation":[{"name":"6School of Medicine, Trinity College, University of Dublin, Dublin, Ireland"},{"name":"7National Children's Cancer Service, Children's Health Ireland at Crumlin, Dublin, Ireland"}]},{"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"}]},{"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"}]},{"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"}]},{"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 Kingdom"}]},{"given":"Thomas A.","family":"Milne","sequence":"additional","affiliation":[{"name":"4MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom"}]},{"given":"Anindita","family":"Roy","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"},{"name":"5Department of Haematology, Great Ormond Street Hospital, London, United Kingdom"}]},{"given":"Anastasios","family":"Karadimitris","sequence":"additional","affiliation":[{"name":"1Centre for Haematology, Department of Immunology and Inflammation, Imperial College London, London, United Kingdom"},{"name":"11Department of Haematology, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, United 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Leukemia","value_numeric":null},{"paper_doi":"10.1182/blood.2025029302","tag_type":"impact_flag","value":"limited_evidence","value_numeric":null},{"paper_doi":"10.1182/blood.2025029302","tag_type":"modality","value":"CAR-iNKT Cell Therapy","value_numeric":null},{"paper_doi":"10.1182/blood.2025029302","tag_type":"study_design","value":"Preclinical Study","value_numeric":null},{"paper_doi":"10.1182/blood.2025029302","tag_type":"warning","value":"Only abstract details available; sample size and numeric outcomes not reported.","value_numeric":null},{"paper_doi":"10.1182/blood.2025029302","tag_type":"warning","value":"Preclinical study (in vitro and animal models); no human clinical outcomes.","value_numeric":null},{"paper_doi":"10.1182/blood.2025029302","tag_type":"warning","value":"Study design label may not map cleanly to standard clinical categories.","value_numeric":null}],"summaries":{"what_studied":"Engineered allogeneic invariant natural killer T (iNKT) cells with CD19 and/or CD133 CARs and compared bispecific CD19–CD133 CAR‑iNKT cells to monospecific CAR‑iNKT and dual/bispecific CAR T cells against KMT2A‑rearranged ALL in in vitro and in vivo models, including leptomeningeal disease.","key_result":"Bispecific CD19–CD133 CAR‑iNKT cells showed stronger antileukemia activity than the comparators, eradicated medullary and leptomeningeal leukemia, produced sustained remissions, and caused no discernible hematologic toxicity in the models; their potency was linked to CAR‑dependent upregulation of NKG2D enabling targeting despite downregulation of CD19 or CD133.","limitations":"Findings are from preclinical in vitro and in vivo models, not human trials; the abstract reports no quantitative efficacy or safety metrics.","practice_takeaway":"No change to practice yet; these preclinical data highlight a potential off‑the‑shelf bispecific CAR‑iNKT approach for KMT2A‑rearranged ALL, including CNS disease, warranting attention to upcoming clinical 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