4.7 Article

Expansion of cytotoxic natural killer cells in multiple myeloma patients using K562 cells expressing OX40 ligand and membrane-bound IL-18 and IL-21

Journal

CANCER IMMUNOLOGY IMMUNOTHERAPY
Volume 71, Issue 3, Pages 613-625

Publisher

SPRINGER
DOI: 10.1007/s00262-021-02982-9

Keywords

Multiple Myeloma; NK cells; OX40L; IL-18; IL-21

Funding

  1. Basic Science Research Program through the National Research Foundation of Korea (NRF) - Ministry of Education, Science and Technology [2018R1A2B6006200, 2020R1A2C2010098]
  2. National Research Foundation of Korea [2018R1A2B6006200, 2020R1A2C2010098] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)

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Genetically engineered K562 cells expressing OX40L, mbIL-18, and mbIL-21 have been shown to improve the expansion of NK cells, increase activation signals, and enhance their cytotoxic activity towards multiple myeloma cells.
Background Natural killer (NK) cell-based immunotherapy is a promising treatment approach for multiple myeloma (MM), but obtaining a sufficient number of activated NK cells remains challenging. Here, we report an improved method to generate ex vivo expanded NK (eNK) cells from MM patients based on genetic engineering of K562 cells to express OX40 ligand and membrane-bound (mb) IL-18 and IL-21. Methods K562-OX40L-mbIL-18/-21 cells were generated by transducing K562-OX40L cells with a lentiviral vector encoding mbIL-18 and mbIL-21, and these were used as feeder cells to expand NK cells from peripheral blood mononuclear cells of healthy donors (HDs) and MM patients in the presence of IL-2/IL-15. Purity, expansion rate, receptor expression, and functions of eNK cells were determined over four weeks of culture. Results NK cell expansion was enhanced by short exposure of soluble IL-18 and IL-21 with K562-OX40L cells. Co-culture of NK cells with K562-OX40L-mbIL-18/-21 cells resulted in remarkable expansion of NK cells from HDs (9,860-fold) and MM patients (4,929-fold) over the 28-day culture period. Moreover, eNK cells showed increased expression of major activation markers and enhanced cytotoxicity towards target K562, U266, and RPMI8226 cells. Conclusions Our data suggest that genetically engineered K562 cells expressing OX40L, mbIL-18, and mbIL-21 improve the expansion of NK cells, increase activation signals, and enhance their cytolytic activity towards MM cells.

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