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IL-18-secreting multiantigen targeting CAR T cells eliminate antigen-low myeloma in an immunocompetent mouse model.
- Source :
-
Blood [Blood] 2024 Jul 11; Vol. 144 (2), pp. 171-186. - Publication Year :
- 2024
-
Abstract
- 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.
- Subjects :
- Animals
Mice
Humans
Receptors, Chimeric Antigen immunology
Disease Models, Animal
Antigens, Neoplasm immunology
T-Lymphocytes immunology
T-Lymphocytes metabolism
Cell Line, Tumor
Multiple Myeloma immunology
Multiple Myeloma therapy
Multiple Myeloma pathology
Interleukin-18 immunology
Immunotherapy, Adoptive methods
B-Cell Maturation Antigen immunology
Subjects
Details
- Language :
- English
- ISSN :
- 1528-0020
- Volume :
- 144
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Blood
- Publication Type :
- Academic Journal
- Accession number :
- 38579288
- Full Text :
- https://doi.org/10.1182/blood.2023022293