IL-18-secreting multiantigen targeting CAR T cells eliminate antigen-low myeloma in an immunocompetent mouse model

• Published in: Blood 2024-07, Vol.144 (2), p.171-186
• Main Authors: Ng, Brandon D., Rajagopalan, Adhithi, Kousa, Anastasia I., Fischman, Jacob S., Chen, Sophia, Massa, Alyssa, Elias, Harold K., Manuele, Dylan, Galiano, Michael, Lemarquis, Andri L., Boardman, Alexander P., DeWolf, Susan, Pierce, Jonah, Bogen, Bjarne, James, Scott E., van den Brink, Marcel R. M.
• Format: Article
• Language: English
• Subjects: Animals; Antigens, Neoplasm - immunology; B-Cell Maturation Antigen - immunology; Cell Line, Tumor; Disease Models, Animal; Humans; Immunotherapy, Adoptive - methods; Interleukin-18 - immunology; Mice; Multiple Myeloma - immunology; Multiple Myeloma - pathology; Multiple Myeloma - therapy; Receptors, Chimeric Antigen - immunology; T-Lymphocytes - immunology; T-Lymphocytes - metabolism
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood.2023022293

•IL-18-secreting CAR T cells promote clearance of antigen-low myeloma with reprogramming of cells in the myeloma microenvironment.•Multiantigen targeting enhances T-cell-target avidity, increasing engineered IL-18 output and potentiating antimyeloma activity. [Display omitted] 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. In multiple myeloma, the currently available chimeric antigen receptor (CAR) T cells do not appear to be curative, and new constructs and approaches are needed. Using immunocompetent mouse models, Ng and colleagues demonstrate that interleukin-18 (IL-18)–secreting CAR T cells promote clearance of antigen-low myeloma with reprogramming of cells in the myeloma microenvironment and that antimyeloma activity ca