嵌合抗原受体
抗原
癌症研究
多发性骨髓瘤
免疫学
骨髓
T细胞
医学
免疫系统
作者
Brandon D. Ng,Adhithi Rajagopalan,Anastasia I. Kousa,Jacob S. Fischman,Sophia Chen,Alyssa Massa,Harold K. Elias,Dylan Manuele,Michael Galiano,Andri L. Lemarquis,Alexander P. Boardman,Susan DeWolf,J W Pierce,Bjarne Bogen,Scott E. James,Marcel R.M. van den Brink
出处
期刊:Blood
[American Society of Hematology]
日期:2024-07-11
卷期号:144 (2): 171-186
被引量:1
标识
DOI:10.1182/blood.2023022293
摘要
Abstract 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–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/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 vivo. Our results demonstrate that combination of engineered IL-18 secretion and multiantigen targeting can eliminate myeloma with weak antigen expression through distinct mechanisms.
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