title: NK cells engineered to express a GD2 -specific antigen receptor display built-in ADCC-like activity against tumour cells of neuroectodermal origin.
abstract: Treatment of high-risk neuroblastoma (NB) represents a major challenge in paediatric oncology. Alternative therapeutic strategies include antibodies targeting the disialoganglioside GD(2) , which is expressed at high levels on NB cells, and infusion of donor-derived natural killer (NK) cells. To combine specific antibody-mediated recognition of NB cells with the potent cytotoxic activity of NK cells, here we generated clonal derivatives of the clinically applicable human NK cell line NK-92 that stably express a GD(2) -specific chimeric antigen receptor (CAR) comprising an anti-GD(2)  ch14.18 single chain Fv antibody fusion protein with CD3-ζ chain as a signalling moiety. CAR expression by gene-modified NK cells facilitated effective recognition and elimination of established GD(2)  expressing NB cells, which were resistant to parental NK-92. In the case of intrinsically NK-sensitive NB cell lines, we observed markedly increased cell killing activity of retargeted NK-92 cells. Enhanced cell killing was strictly dependent on specific recognition of the target antigen and could be blocked by GD(2) -specific antibody or anti-idiotypic antibody occupying the CAR's cell recognition domain. Importantly, strongly enhanced cytotoxicity of the GD(2) -specific NK cells was also found against primary NB cells and GD(2)  expressing tumour cells of other origins, demonstrating the potential clinical utility of the retargeted effector cells.
authors: Pediatric Hematology and Oncology, University Hospital, Frankfurt am Main, Germany.
authors: Ruth
authors: R
authors: Esser
authors: Tina
authors: T
authors: Müller
authors: Dörthe
authors: D
authors: Stefes
authors: Stephan
authors: S
authors: Kloess
authors: Diana
authors: D
authors: Seidel
authors: Stephen D
authors: SD
authors: Gillies
authors: Christel
authors: C
authors: Aperlo-Iffland
authors: James S
authors: JS
authors: Huston
authors: Christoph
authors: C
authors: Uherek
authors: Kurt
authors: K
authors: Schönfeld
authors: Torsten
authors: T
authors: Tonn
authors: Nicole
authors: N
authors: Huebener
authors: Holger N
authors: HN
authors: Lode
authors: Ulrike
authors: U
authors: Koehl
authors: Winfried S
authors: WS
authors: Wels
references: Cytotherapy. 2008;10(6):625-32
references: 18836917
references: Lancet Oncol. 2008 Mar;9(3):247-56
references: 18308250
references: Cancer Immunol Immunother. 2004 Mar;53(3):217-26
references: 14704833
references: J Clin Oncol. 2010 Nov 20;28(33):4969-75
references: 20921469
references: Lancet Oncol. 2005 Sep;6(9):649-58
references: 16129365
references: Mol Imaging. 2009 Jan-Feb;8(1):15-26
references: 19344572
references: Pain. 2010 Apr;149(1):135-142
references: 20171010
references: Int J Cancer. 2001 Oct 15;94(2):228-36
references: 11668503
references: Nat Immunol. 2008 May;9(5):495-502
references: 18425106
references: Clin Cancer Res. 1996 Jun;2(6):1001-8
references: 9816261
references: Cancer Immunol Immunother. 2002 Apr;51(2):107-10
references: 11904735
references: Cancer Immunol Immunother. 2008 Mar;57(3):411-23
references: 17717662
references: Clin Cancer Res. 1997 Nov;3(11):1969-76
references: 9815586
references: J Immunother. 2010 Feb-Mar;33(2):200-10
references: 20145545
references: J Clin Oncol. 2004 Sep 1;22(17):3549-57
references: 15337804
references: Nat Med. 2008 Nov;14(11):1264-70
references: 18978797
references: Biol Blood Marrow Transplant. 1996 May;2(2):68-75
references: 9118301
references: J Immunol Methods. 1989 Dec 20;125(1-2):191-202
references: 2514231
references: Nat Immunol. 2008 May;9(5):486-94
references: 18425105
references: Blood. 2002 Feb 1;99(3):754-8
references: 11806974
references: Clin Cancer Res. 1998 Sep;4(9):2135-9
references: 9748131
references: J Hematother Stem Cell Res. 2001 Aug;10(4):535-44
references: 11522236
references: J Clin Oncol. 2008 Apr 10;26(11):1789-96
references: 18347005
references: J Immunol Methods. 2007 Aug 31;325(1-2):140-7
references: 17663991
references: Neoplasia. 2004 Sep-Oct;6(5):558-68
references: 15548365
references: J Immunol Methods. 2005 Jan;296(1-2):63-76
references: 15680151
references: Curr Cancer Drug Targets. 2010 Mar;10(2):200-9
references: 20201786
references: Pediatr Blood Cancer. 2008 Dec;51(6):747-53
references: 18704922
references: Cancer Invest. 2007 Feb;25(1):67-77
references: 17364560
references: J Clin Oncol. 2000 Dec 15;18(24):4077-85
references: 11118469
references: Nat Rev Immunol. 2005 Dec;5(12):928-40
references: 16322746
references: Eur J Immunol. 2010 Nov;40(11):3255-67
references: 21061445
references: J Cell Biol. 1986 Mar;102(3):688-96
references: 3005335
references: J Clin Oncol. 2009 Mar 1;27(7):1007-13
references: 19171716
references: Nat Rev Cancer. 2002 Nov;2(11):850-61
references: 12415255
references: Mol Immunol. 2005 Feb;42(4):501-10
references: 15607806
references: Leukemia. 1994 Apr;8(4):652-8
references: 8152260
references: J Hematother. 1999 Jun;8(3):281-90
references: 10417052
references: Clin Cancer Res. 1998 Nov;4(11):2859-68
references: 9829753
references: J Exp Med. 1987 Mar 1;165(3):812-29
references: 3102678
references: Clin Cancer Res. 2009 Aug 1;15(15):4857-66
references: 19638467
references: J Virol Methods. 1999 Aug;81(1-2):71-5
references: 10488763
references: J Hematother Stem Cell Res. 2001 Jun;10(3):369-83
references: 11454312
references: Blood. 2002 Aug 15;100(4):1265-73
references: 12149207
references: Cancer Treat Rev. 2010 Jun;36(4):307-17
references: 20227189
references: N Engl J Med. 2010 Sep 30;363(14):1324-34
references: 20879881
references: Cancer Res. 1984 Dec;44(12 Pt 1):5914-20
references: 6498849
references: J Immunol. 1990 Feb 15;144(4):1382-6
references: 2303711
references: Cancer Lett. 1993 Jun 15;70(1-2):15-24
references: 8330296
references: Pediatr Blood Cancer. 2009 Dec;53(6):931-40
references: 19591222
references: Eur J Cancer. 1995;31A(2):261-7
references: 7718335