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den Brink, Immunology, Memorial Sloan Kettering Cancer Center"],"full_dataset_link":["https://www.ebi.ac.uk/ena/browser/view/PRJNA1089207"],"scientific_name":["Mus musculus"],"tag":["xref:PubMed:38579288"],"long_description":["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 low expression of BCMA on myeloma cells, suggesting that novel approaches to better address antigen-low disease may improve patient outcomes. We hypothesized that engineered secretion of the pro-inflammatory cytokine interleukin-18 (IL-18) and multi-antigen 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 (BAFF-R) failed to eliminate myeloma when these antigens were weakly expressed. In contrast, IL-18-secreting 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 and II interferon signaling, and utilized macrophages to mediate anti-myeloma 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 anti-myeloma activity. Dual-antigen targeting augmented CAR T-cell secretion of engineered IL-18 and facilitated elimination of larger myeloma burdens in vivo. Our results demonstrate that combination of engineered IL-18 secretion and multi-antigen targeting can eliminate myeloma with weak antigen expression through distinct mechanisms. Overall design: scRNA of APRIL CAR T cells +/- engineered IL-18 secretion following stimulation with MOPC315.BM."],"repository":["ENA"],"additional_accession":[]},"is_claimable":false,"name":"IL-18-secreting multi-antigen targeting CAR T-cells eliminate antigen-low myeloma in an immunocompetent mouse model [in vitro]","description":"IL-18-secreting multi-antigen targeting CAR T-cells eliminate antigen-low myeloma in an immunocompetent mouse model [in vitro]","dates":{"last_updated":"2025-09-24","first_public":"2024-05-17"},"accession":"PRJNA1089207","cross_references":{"GEO":["GSE261852"],"taxon":["10090"],"PubMed":["38579288"]}}