Highly activated and expanded natural killer cells for multiple myeloma immunotherapy. Academic Article uri icon

abstract

  • BACKGROUND: Patients with gene expression profiling-defined high-risk myeloma in relapse have poor outcomes with current therapies. We tested whether natural killer cells expanded by co-culture with K562 cells transfected with 41BBL and membrane-bound interleukin-15 could kill myeloma cells with a high-risk gene expression profile in vitro and in a unique model which recapitulates human myeloma. DESIGN AND METHODS: OPM2 and high-risk primary myeloma tumors were grown in human fetal bone implanted into non-obese diabetic severe combined immunodeficiency mice with a deficient interleukin-2 receptor gamma chain. These mice are devoid of endogenous natural killer and T-cell activity and were used to determine whether adoptively transferred expanded natural killer cells could inhibit myeloma growth and myeloma-associated bone destruction. RESULTS: Natural killer cells from healthy donors and myeloma patients expanded a median of 804- and 351-fold, respectively, without significant T-cell expansion. Expanded natural killer cells killed both allogeneic and autologous primary myeloma cells avidly via a perforin-mediated mechanism in which the activating receptor NKG2D, natural cytotoxicity receptors, and DNAX-accessory molecule-1 played a central role. Adoptive transfer of expanded natural killer cells inhibited the growth of established OPM2 and high-risk primary myeloma tumors grown in the murine model. The transferred, expanded natural killer cells proliferated in vivo in an interleukin-2 dose-dependent fashion, persisted up to 4 weeks, were readily detectable in the human bone, inhibited myeloma growth and protected bone from myeloma-induced osteolysis. CONCLUSIONS: These studies provide the rationale for testing expanded natural killer cells in humans.

published proceedings

  • Haematologica

altmetric score

  • 9

author list (cited authors)

  • Garg, T. K., Szmania, S. M., Khan, J. A., Hoering, A., Malbrough, P. A., Moreno-Bost, A., ... van Rhee, F

citation count

  • 82

complete list of authors

  • Garg, Tarun K||Szmania, Susann M||Khan, Junaid A||Hoering, Antje||Malbrough, Paul A||Moreno-Bost, Amberly||Greenway, Amy D||Lingo, Joshuah D||Li, Xin||Yaccoby, Shmuel||Suva, Larry J||Storrie, Brian||Tricot, Guido||Campana, Dario||Shaughnessy, John D||Nair, Bijay P||Bellamy, William T||Epstein, Joshua||Barlogie, Bart||van Rhee, Frits

publication date

  • March 2012