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Expanded natural killer cells augment the antimyeloma effect of daratumumab, bortezomib, and dexamethasone in a mouse model

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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References

  1. Roodman, G. D. Pathogenesis of myeloma bone disease. Leukemia 23, 435ā€“441 (2009).

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  2. Rajkumar, S. V. & Kumar, S. Multiple myeloma: diagnosis and treatment. Mayo Clin. Proc. 91, 101ā€“119 (2016).

    ArticleĀ  PubMedĀ  Google ScholarĀ 

  3. Al-Hujaily E. M., Oldham R. A., Hari P., Medin J. A. Development of Novel Immunotherapies for Multiple Myeloma. Int. J. Mol. Sci. 17, 1506 https://doi.org/10.3390/ijms17091506 (2016).

  4. Berahovich R., et al. CAR-T Cells Based on Novel BCMA Monoclonal Antibody Block Multiple Myeloma Cell Growth. Cancers (Basel). 10, 323 https://doi.org/10.3390/cancers10090323 (2018).

  5. Leung, W. Infusions of allogeneic natural killer cells as cancer therapy. Clin. Cancer Res. 20, 3390ā€“3400 (2014).

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  6. Garg, T. K. et al. Highly activated and expanded natural killer cells for multiple myeloma immunotherapy. Haematologica 97, 1348ā€“1356 (2012).

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  7. Jung, I. H. et al. In Vivo Study of Natural Killer (NK) Cell Cytotoxicity Against Cholangiocarcinoma in a Nude Mouse Model. Vivo 32, 771ā€“781. (2018).

    ArticleĀ  CASĀ  Google ScholarĀ 

  8. Pittari, G. et al. Restoring Natural Killer Cell Immunity against Multiple Myeloma in the Era of New Drugs. Front. Immunol. 8, 1444 (2017).

    ArticleĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  9. Mahaweni, N. M., Ehlers, F. A. I., Bos, G. M. J. & Wieten, L. Tuning Natural Killer Cell Anti-multiple Myeloma Reactivity by Targeting Inhibitory Signaling via KIR and NKG2A. Front. Immunol. 9, 2848 (2018).

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  10. Shi, J. et al. Bortezomib down-regulates the cell-surface expression of HLA class I and enhances natural killer cell-mediated lysis of myeloma. Blood 111, 1309ā€“1317 (2008).

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  11. Luna, J. I. et al. Bortezomib Augments Natural Killer Cell Targeting of Stem-Like Tumor Cells. Cancers (Basel) 11, 85 (2019). 11.

    ArticleĀ  CASĀ  Google ScholarĀ 

  12. de Weers, M. et al. Daratumumab, a novel therapeutic human CD38 monoclonal antibody, induces killing of multiple myeloma and other hematological tumors. J. Immunol. (Baltim., Md: 1950) 186, 1840ā€“1848 (2011).

    ArticleĀ  Google ScholarĀ 

  13. Plesner, T. & Krejcik, J. Daratumumab for the Treatment of Multiple Myeloma. Front. Immunol. 9, 1228 (2018).

    ArticleĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  14. Nijhof, I. S. et al. Daratumumab-mediated lysis of primary multiple myeloma cells is enhanced in combination with the human anti-KIR antibody IPH2102 and lenalidomide. Haematologica 100, 263ā€“268 (2015).

    ArticleĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  15. Hofmeister, C. C. & Lonial, S. How to Integrate Elotuzumab and Daratumumab Into Therapy for Multiple Myeloma. J. Clin. Oncol. 34, 4421ā€“4430. (2016).

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  16. Li, Y., Hermanson, D. L., Moriarity, B. S. & Kaufman, D. S. Human iPSC-Derived Natural Killer Cells Engineered with Chimeric Antigen Receptors Enhance Anti-tumor Activity. Cell. Stem Cell. 23, 181ā€“192 (2018). e5.

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  17. Kim, K. W. et al. Combined NK Cell Therapy and Radiation Therapy Exhibit Long-Term Therapeutic and Antimetastatic Effects in a Human Triple Negative Breast Cancer Model. Int J. Radiat. Oncol. Biol. Phys. 108, 115ā€“125. (2020).

    ArticleĀ  PubMedĀ  Google ScholarĀ 

  18. Miyazaki, O. et al. Antimyeloma activity of NK012, a micelle-forming macromolecular prodrug of SN-38, in an orthotopic model. Int J. Cancer 134, 218ā€“223 (2014).

    ArticleĀ  PubMedĀ  Google ScholarĀ 

  19. Gras Navarro A., et al. Pretreatment of Glioblastoma with Bortezomib Potentiates Natural Killer Cell Cytotoxicity through TRAIL/DR5 Mediated Apoptosis and Prolongs Animal Survival. Cancers. 11, 996 https://doi.org/10.3390/cancers11070996 (2019).

  20. Wang, Y. et al. Fratricide of NK Cells in Daratumumab Therapy for Multiple Myeloma Overcome by Ex Vivo-Expanded Autologous NK Cells. Clin. Cancer Res. 24, 4006ā€“4017. (2018).

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  21. Wang, Q. M. et al. Enhanced Cancer Immunotherapy with Smad3-Silenced NK-92 Cells. Cancer Immunol. Res. 6, 965ā€“977. (2018).

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  22. Chesi, M. et al. Drug response in a genetically engineered mouse model of multiple myeloma is predictive of clinical efficacy. Blood 120, 376ā€“385 (2012).

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  23. Rezvani, K. & Rouce, R. H. The Application of Natural Killer Cell Immunotherapy for the Treatment of Cancer. Front. Immunol. 6, 578 (2015).

    ArticleĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  24. Liu, E. et al. Use of CAR-Transduced Natural Killer Cells in CD19-Positive Lymphoid Tumors. N. Engl. J. Med. 382, 545ā€“553. (2020).

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  25. Leivas, A. et al. Novel treatment strategy with autologous activated and expanded natural killer cells plus anti-myeloma drugs for multiple myeloma. Oncoimmunology 5, e1250051 (2016).

    ArticleĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  26. Shanker, A. et al. Bortezomib Improves Adoptive T-cell Therapy by Sensitizing Cancer Cells to FasL Cytotoxicity. Cancer Res. 75, 5260ā€“5272 (2015).

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  27. Carlsten, M. et al. Bortezomib sensitizes multiple myeloma to NK cells via ER-stress-induced suppression of HLA-E and upregulation of DR5. Oncoimmunology 8, e1534664 (2019).

    ArticleĀ  PubMedĀ  Google ScholarĀ 

  28. Kamiya, T., Seow, S. V., Wong, D., Robinson, M. & Campana, D. Blocking expression of inhibitory receptor NKG2A overcomes tumor resistance to NK cells. J. Clin. Investig. 129, 2094ā€“2106. (2019).

    ArticleĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  29. Niehrs, A. & Altfeld, M. Regulation of NK-Cell Function by HLA Class II. Front. Cell Infect. Microbiol. 10, 55 (2020).

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  30. Schreeder, D. M. et al. Cutting edge: FcR-like 6 is an MHC class II receptor. J. Immunol. (Baltim., Md: 1950) 185, 23ā€“27 (2010).

    ArticleĀ  CASĀ  Google ScholarĀ 

  31. Johnson, D. B. et al. Tumor-specific MHC-II expression drives a unique pattern of resistance to immunotherapy via LAG-3/FCRL6 engagement. JCI Insight 3, e120360 (2018).

    ArticleĀ  PubMed CentralĀ  Google ScholarĀ 

  32. Verkleij C. P. M., et al. Preclinical Rationale for Targeting the PD-1/PD-L1 Axis in Combination with a CD38 Antibody in Multiple Myeloma and Other CD38-Positive Malignancies. Cancers. 12, 3713 https://doi.org/10.3390/cancers12123713 2020.

  33. Ochoa, M. C. et al. Daratumumab in combination with urelumab to potentiate anti-myeloma activity in lymphocyte-deficient mice reconstituted with human NK cells. Oncoimmunology 8, 1599636 (2019).

    ArticleĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  34. Reina-Ortiz, C. et al. Expanded NK cells from umbilical cord blood and adult peripheral blood combined with daratumumab are effective against tumor cells from multiple myeloma patients. Oncoimmunology 10, 1853314 (2020).

    ArticleĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  35. Granzin, M. et al. Shaping of Natural Killer Cell Antitumor Activity by Ex Vivo Cultivation. Front. Immunol. 8, 458 (2017).

    ArticleĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  36. Zhang, Y. et al. In vivo kinetics of human natural killer cells: the effects of ageing and acute and chronic viral infection. Immunology 121, 258ā€“265 (2007).

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  37. Fujisaki, H. et al. Expansion of highly cytotoxic human natural killer cells for cancer cell therapy. Cancer Res. 69, 4010ā€“4017 (2009).

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  38. Denman, C. J. et al. Membrane-bound IL-21 promotes sustained ex vivo proliferation of human natural killer cells. PLoS ONE 7, e30264 (2012).

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  39. Seo, H. et al. IL-21-mediated reversal of NK cell exhaustion facilitates anti-tumour immunity in MHC class I-deficient tumours. Nat. Commun. 8, 15776 (2017).

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  40. Lim, D. P. et al. Effect of exposure to interleukin-21 at various time points on human natural killer cell culture. Cytotherapy 16, 1419ā€“1430 (2014).

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  41. Imai, C., Iwamoto, S. & Campana, D. Genetic modification of primary natural killer cells overcomes inhibitory signals and induces specific killing of leukemic cells. Blood 106, 376ā€“383 (2005).

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  42. Senju, H. et al. Effect of IL-18 on the Expansion and Phenotype of Human Natural Killer Cells: application to Cancer Immunotherapy. Int J. Biol. Sci. 14, 331ā€“340. (2018).

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  43. Geller, M. A. et al. Intraperitoneal delivery of human natural killer cells for treatment of ovarian cancer in a mouse xenograft model. Cytotherapy 15, 1297ā€“1306 (2013).

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  44. Oyer, J. L. et al. Natural killer cells stimulated with PM21 particles expand and biodistribute in vivo: clinical implications for cancer treatment. Cytotherapy 18, 653ā€“663 (2016).

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  45. Imamura, M. et al. Autonomous growth and increased cytotoxicity of natural killer cells expressing membrane-bound interleukin-15. Blood 124, 1081ā€“1088 (2014).

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  46. Liu, E. et al. Cord blood NK cells engineered to express IL-15 and a CD19-targeted CAR show long-term persistence and potent antitumor activity. Leukemia 32, 520ā€“531. (2018).

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  47. Ciurea, S. O. et al. Phase 1 clinical trial using mbIL21 ex vivo-expanded donor-derived NK cells after haploidentical transplantation. Blood 130, 1857ā€“1868. (2017).

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  48. Lee, S. C. et al. Phase I Trial of Expanded, Activated Autologous NK-cell Infusions with Trastuzumab in Patients with HER2-positive Cancers. Clin. Cancer Res. 26, 4494ā€“4502. (2020).

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

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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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Correspondence to Duck Cho or Je-Jung Lee.

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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, 1652ā€“1661 (2021). https://doi.org/10.1038/s41423-021-00686-9

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