IL-18-secreting multiantigen targeting CAR T cells eliminate antigen-low myeloma in an immunocompetent mouse model Journal Article
| Authors: | Ng, B. D.; Rajagopalan, A.; Kousa, A. I.; Fischman, J. S.; Chen, S.; Massa, A.; Elias, H. K.; Manuele, D.; Galiano, M.; Lemarquis, A. L.; Boardman, A. P.; DeWolf, S.; Pierce, J.; Bogen, B.; James, S. E.; van den Brink, M. R. M. |
| Article Title: | IL-18-secreting multiantigen targeting CAR T cells eliminate antigen-low myeloma in an immunocompetent mouse model |
| 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. © 2024 |
| Keywords: | controlled study; nonhuman; antigen expression; t lymphocyte; t-lymphocytes; mouse; animal; metabolism; animals; mice; cell survival; multiple myeloma; bone marrow; animal experiment; animal model; immunoglobulin enhancer binding protein; in vivo study; antineoplastic activity; pathology; cell line, tumor; tumor antigen; disease model; immunology; antigens, neoplasm; gamma interferon; tumor cell line; chimeric antigen receptor; cytokine production; disease models, animal; cytokine release; therapy; adoptive immunotherapy; immunotherapy, adoptive; interleukin 18; tumor microenvironment; macrophage activation; procedures; b cell activating factor receptor; interleukin-18; humans; human; article; b cell maturation antigen; b-cell maturation antigen; chimeric antigen receptor t-cell immunotherapy; receptors, chimeric antigen; cell therapy agent; nf kb signaling; type i interferon signaling; type ii interferon signaling |
| Journal Title: | Blood |
| Volume: | 144 |
| Issue: | 2 |
| ISSN: | 0006-4971 |
| Publisher: | American Society of Hematology |
| Date Published: | 2024-07-11 |
| Start Page: | 171 |
| End Page: | 186 |
| Language: | English |
| DOI: | 10.1182/blood.2023022293 |
| PUBMED: | 38579288 |
| PROVIDER: | scopus |
| PMCID: | PMC11302468 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledge in the PDF -- Corresponding authors are MSK author: Marcel R. M. van den Brink and Scott E. James -- Source: Scopus |
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