title: Antigen presenting cell-mediated expansion of human umbilical cord blood yields log-scale expansion of natural killer cells with anti-myeloma activity.
abstract: Natural killer (NK) cells are important mediators of anti-tumor immunity and are active against several hematologic malignancies, including multiple myeloma (MM). Umbilical cord blood (CB) is a promising source of allogeneic NK cells but large scale ex vivo expansion is required for generation of clinically relevant CB-derived NK (CB-NK) cell doses. Here we describe a novel strategy for expanding NK cells from cryopreserved CB units using artificial antigen presenting feeder cells (aAPC) in a gas permeable culture system. After 14 days, mean fold expansion of CB-NK cells was 1848-fold from fresh and 2389-fold from cryopreserved CB with >95% purity for NK cells (CD56(+)/CD3(-)) and less than 1% CD3(+) cells. Though surface expression of some cytotoxicity receptors was decreased, aAPC-expanded CB-NK cells exhibited a phenotype similar to CB-NK cells expanded with IL-2 alone with respect to various inhibitory receptors, NKG2C and CD94 and maintained strong expression of transcription factors Eomesodermin and T-bet. Furthermore, CB-NK cells formed functional immune synapses with and demonstrated cytotoxicity against various MM targets. Finally, aAPC-expanded CB-NK cells showed significant in vivo activity against MM in a xenogenic mouse model. Our findings introduce a clinically applicable strategy for the generation of highly functional CB-NK cells which can be used to eradicate MM.
authors.affiliation: Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Nina
authors.initials: N
authors.lastname: Shah
authors.forename: Beatriz
authors.initials: B
authors.lastname: Martin-Antonio
authors.forename: Hong
authors.initials: H
authors.lastname: Yang
authors.forename: Stephanie
authors.initials: S
authors.lastname: Ku
authors.forename: Dean A
authors.initials: DA
authors.lastname: Lee
authors.forename: Laurence J N
authors.initials: LJ
authors.lastname: Cooper
authors.forename: William K
authors.initials: WK
authors.lastname: Decker
authors.forename: Sufang
authors.initials: S
authors.lastname: Li
authors.forename: Simon N
authors.initials: SN
authors.lastname: Robinson
authors.forename: Takuya
authors.initials: T
authors.lastname: Sekine
authors.forename: Simrit
authors.initials: S
authors.lastname: Parmar
authors.forename: John
authors.initials: J
authors.lastname: Gribben
authors.forename: Michael
authors.initials: M
authors.lastname: Wang
authors.forename: Katy
authors.initials: K
authors.lastname: Rezvani
authors.forename: Eric
authors.initials: E
authors.lastname: Yvon
authors.forename: Amer
authors.initials: A
authors.lastname: Najjar
authors.forename: Jared
authors.initials: J
authors.lastname: Burks
authors.forename: Indreshpal
authors.initials: I
authors.lastname: Kaur
authors.forename: Richard E
authors.initials: RE
authors.lastname: Champlin
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Bollard
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Shpall
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology*; D017252:CD3 Complex / Q000276:immunology / Q000378:metabolism; D019002:CD56 Antigen / Q000276:immunology / Q000378:metabolism; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002478:Cells, Cultured; D018920:Coculture Techniques; D003602:Cytotoxicity, Immunologic / Q000187:drug effects / Q000276:immunology; D005312:Fetal Blood / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D053631:Interleukin Receptor Common gamma Subunit / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D007376:Interleukin-2 / Q000276:immunology / Q000494:pharmacology; D020014:K562 Cells; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D018613:Microscopy, Confocal; D009101:Multiple Myeloma / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D055654:NK Cell Lectin-Like Receptor Subfamily C / Q000276:immunology / Q000378:metabolism; D051920:NK Cell Lectin-Like Receptor Subfamily D / Q000276:immunology / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D017252:CD3 Complex; D019002:CD56 Antigen; D053631:Interleukin Receptor Common gamma Subunit; D007376:Interleukin-2; C527059:KLRC2 protein, human; D055654:NK Cell Lectin-Like Receptor Subfamily C; D051920:NK Cell Lectin-Like Receptor Subfamily D