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Haematologica. 2012 Sep;97(9):1348-56. doi: 10.3324/haematol.2011.056747. Epub 2012 Mar 14.

Highly activated and expanded natural killer cells for multiple myeloma immunotherapy.

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  • 1Myeloma Institute for Research and Therapy University of Arkansas for Medical Sciences 4301 West Markham, Little Rock, AR 72205 USA.

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.

PMID:
22419581
[PubMed - in process]
PMCID:
PMC3436235
Free PMC Article
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