Highly activated and expanded natural killer cells for multiple myeloma immunotherapy.
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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.
author list (cited authors)
Garg, T. K., Szmania, S. M., Khan, J. A., Hoering, A., Malbrough, P. A., Moreno-Bost, A., ... van Rhee, F.
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