title: Highly activated and expanded natural killer cells for multiple myeloma immunotherapy.
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.
  
  
  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.
authors.affiliation: Myeloma Institute for Research and Therapy University of Arkansas for Medical Sciences 4301 West Markham, Little Rock, AR 72205 USA.
authors.forename: Tarun K
authors.initials: TK
authors.lastname: Garg
authors.forename: Susann M
authors.initials: SM
authors.lastname: Szmania
authors.forename: Junaid A
authors.initials: JA
authors.lastname: Khan
authors.forename: Antje
authors.initials: A
authors.lastname: Hoering
authors.forename: Paul A
authors.initials: PA
authors.lastname: Malbrough
authors.forename: Amberly
authors.initials: A
authors.lastname: Moreno-Bost
authors.forename: Amy D
authors.initials: AD
authors.lastname: Greenway
authors.forename: Joshuah D
authors.initials: JD
authors.lastname: Lingo
authors.forename: Xin
authors.initials: X
authors.lastname: Li
authors.forename: Shmuel
authors.initials: S
authors.lastname: Yaccoby
authors.forename: Larry J
authors.initials: LJ
authors.lastname: Suva
authors.forename: Brian
authors.initials: B
authors.lastname: Storrie
authors.forename: Guido
authors.initials: G
authors.lastname: Tricot
authors.forename: Dario
authors.initials: D
authors.lastname: Campana
authors.forename: John D
authors.initials: JD
authors.lastname: Shaughnessy
authors.forename: Bijay P
authors.initials: BP
authors.lastname: Nair
authors.forename: William T
authors.initials: WT
authors.lastname: Bellamy
authors.forename: Joshua
authors.initials: J
authors.lastname: Epstein
authors.forename: Bart
authors.initials: B
authors.lastname: Barlogie
authors.forename: Frits
authors.initials: F
authors.lastname: van Rhee
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D049109:Cell Proliferation; D018920:Coculture Techniques; D003602:Cytotoxicity, Immunologic / Q000276:immunology*; D005434:Flow Cytometry; D006801:Humans; D007124:Immunoenzyme Techniques; D016219:Immunotherapy, Adoptive; D053631:Interleukin Receptor Common gamma Subunit / Q000235:genetics; D007376:Interleukin-2 / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000378:metabolism; D010014:Osteolysis; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D053631:Interleukin Receptor Common gamma Subunit; D007376:Interleukin-2; D055655:NK Cell Lectin-Like Receptor Subfamily K