{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T16:54:10Z","timestamp":1793120050556,"version":"4.5.0"},"reference-count":96,"publisher":"American Society of Hematology","issue":"2","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2024,7,11]]},"abstract":"<jats:sec>\n                  <jats:title>Abstract<\/jats:title>\n                  <jats:p>Multiple myeloma is a plasma cell malignancy that is currently incurable with conventional therapies. Following the success of CD19-targeted chimeric antigen receptor (CAR) T cells in leukemia and lymphoma, CAR T cells targeting B-cell maturation antigen (BCMA) more recently demonstrated impressive activity in relapsed and refractory myeloma patients. However, BCMA-directed therapy can fail due to weak expression of BCMA on myeloma cells, suggesting that novel approaches to better address this antigen-low disease may improve patient outcomes. We hypothesized that engineered secretion of the proinflammatory cytokine interleukin-18 (IL-18) and multiantigen targeting could improve CAR T-cell activity against BCMA-low myeloma. In a syngeneic murine model of myeloma, CAR T cells targeting the myeloma-associated antigens BCMA and B-cell activating factor receptor (BAFF-R) failed to eliminate myeloma when these antigens were weakly expressed, whereas IL-18\u2013secreting CAR T cells targeting these antigens promoted myeloma clearance. IL-18-secreting CAR T cells developed an effector-like T-cell phenotype, promoted interferon-gamma production, reprogrammed the myeloma bone marrow microenvironment through type-I\/II interferon signaling, and activated macrophages to mediate antimyeloma activity. Simultaneous targeting of weakly-expressed BCMA and BAFF-R with dual-CAR T cells enhanced T-cell:target-cell avidity, increased overall CAR signal strength, and stimulated antimyeloma activity. Dual-antigen targeting augmented CAR T-cell secretion of engineered IL-18 and facilitated elimination of larger myeloma burdens in\u00a0vivo. Our results demonstrate that combination of engineered IL-18 secretion and multiantigen targeting can eliminate myeloma with weak antigen expression through distinct mechanisms.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1182\/blood.2023022293","type":"journal-article","created":{"date-parts":[[2024,4,5]],"date-time":"2024-04-05T21:20:31Z","timestamp":1712352031000},"page":"171-186","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":44,"title":["IL-18-secreting multiantigen targeting CAR T cells eliminate antigen-low myeloma in an immunocompetent mouse model"],"prefix":"10.1182","volume":"144","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-8614-9457","authenticated-orcid":false,"given":"Brandon D.","family":"Ng","sequence":"first","affiliation":[{"name":"1Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY"},{"name":"2Department of Pharmacology, Weill Cornell Medicine, New York, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9251-0416","authenticated-orcid":false,"given":"Adhithi","family":"Rajagopalan","sequence":"additional","affiliation":[{"name":"1Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4550-0389","authenticated-orcid":false,"given":"Anastasia I.","family":"Kousa","sequence":"additional","affiliation":[{"name":"1Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY"},{"name":"3City of Hope Comprehensive Cancer Center, Duarte, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6907-5033","authenticated-orcid":false,"given":"Jacob S.","family":"Fischman","sequence":"additional","affiliation":[{"name":"1Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY"},{"name":"4Immunology Graduate Group, University of Pennsylvania, Philadelphia, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6059-0661","authenticated-orcid":false,"given":"Sophia","family":"Chen","sequence":"additional","affiliation":[{"name":"1Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7514-3573","authenticated-orcid":false,"given":"Alyssa","family":"Massa","sequence":"additional","affiliation":[{"name":"1Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY"},{"name":"3City of Hope Comprehensive Cancer Center, Duarte, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6189-4752","authenticated-orcid":false,"given":"Harold K.","family":"Elias","sequence":"additional","affiliation":[{"name":"1Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY"},{"name":"5Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7054-6709","authenticated-orcid":false,"given":"Dylan","family":"Manuele","sequence":"additional","affiliation":[{"name":"1Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY"},{"name":"6Weill Cornell Medical College, New York, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4414-0358","authenticated-orcid":false,"given":"Michael","family":"Galiano","sequence":"additional","affiliation":[{"name":"7Molecular Cytology Core, Memorial Sloan Kettering Cancer Center, New York, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5165-0247","authenticated-orcid":false,"given":"Andri L.","family":"Lemarquis","sequence":"additional","affiliation":[{"name":"1Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7169-9275","authenticated-orcid":false,"given":"Alexander P.","family":"Boardman","sequence":"additional","affiliation":[{"name":"8Lymphoma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2754-3537","authenticated-orcid":false,"given":"Susan","family":"DeWolf","sequence":"additional","affiliation":[{"name":"9Department of Medicine, Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-1029-8748","authenticated-orcid":false,"given":"Jonah","family":"Pierce","sequence":"additional","affiliation":[{"name":"1Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY"},{"name":"10Department of Immunology and Microbial Pathogenesis, Weill Cornell Medicine, New York, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5387-7461","authenticated-orcid":false,"given":"Bjarne","family":"Bogen","sequence":"additional","affiliation":[{"name":"11Oslo University Hospital, Oslo, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3601-6819","authenticated-orcid":false,"given":"Scott E.","family":"James","sequence":"additional","affiliation":[{"name":"1Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, 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