Abstract
The use of natural killer (NK) cells is a promising and safe immunotherapeutic approach in the field of cancer immunotherapy. However, combination treatments are required to enhance the effector functions and therapeutic efficacy of NK cells. In this study, we investigated the potential of daratumumab (Dara), bortezomib, and dexamethasone (Dvd) to augment the antitumor effects of NK cells in a multiple myeloma (MM) xenograft mouse model. NK cells were expanded and activated using the K562-OX40 ligand and membrane-bound IL-18 and IL-21 in the presence of IL-2 and IL-15 from peripheral blood mononuclear cells from MM patients. A human MM xenograft model was established using human RPMI8226-RFP-FLuc cells in NOD/SCID IL-2RĪ³null (NSG) mice. Tumor-bearing mice were divided into six treatment groups: no treatment, expanded NK cells (eNKs), Dara, Dara + eNKs, Dvd, and Dvd + eNKs. Dvd treatment strongly enhanced the cytotoxicity of eNKs by upregulating expression of NK cell activation ligands, downregulating expression of NK cell inhibitory ligands, and promoting antibody-dependent cellular cytotoxicity. The combination of eNKs with Dvd significantly prolonged mouse survival and reduced the tumor burden and serum M-protein level. Furthermore, Dvd pretreatment significantly increased eNK persistence and homing to MM sites. Our findings suggest that Dvd treatment potentiates the antimyeloma effects of NK cells expanded and activated ex vivo by modulating immune responses in MM-bearing mice.
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Acknowledgements
This study was supported by grants from the Basic Science Research Program through the National Research Foundation of Korea (NRF), funded by the Ministry of Education, Science and Technology (2018R1A2B6006200, 2018R1A5A2024181, and 2020R1A2C2010098).
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J.L.T., S.H.J., D.C., J.J.L. designed the study. J.L.T., M.C.V., T.H.C., M.T.T., and K.H.L. performed the experiments and interpreted the data. S.Y.A., M.K., G.Y.S., D.H.Y., J.S.A., and H.J.K. contributed intellectually to the study. J.L.T., S.Y.A., M.C.V., and T.H.C. wrote the paper. D.C. and J.J.L. supervised the study and wrote the paper.
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Thangaraj, J.L., Ahn, SY., Jung, SH. et al. Expanded natural killer cells augment the antimyeloma effect of daratumumab, bortezomib, and dexamethasone in a mouse model. Cell Mol Immunol 18, 1652ā1661 (2021). https://doi.org/10.1038/s41423-021-00686-9
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DOI: https://doi.org/10.1038/s41423-021-00686-9
