Open AccessNK cells engineered to express a GD 2 ‐specific antigen receptor display built‐in ADCC‐like activity against tumour cells of neuroectodermal origin
Author(s) -
Esser Ruth,
Müller Tina,
Stefes Dörthe,
Kloess Stephan,
Seidel Diana,
Gillies Stephen D.,
AperloIffland Christel,
Huston James S.,
Uherek Christoph,
Schönfeld Kurt,
Tonn Torsten,
Huebener Nicole,
Lode Holger N.,
Koehl Ulrike,
Wels Winfried S.
Publication year - 2012
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/j.1582-4934.2011.01343.x
Subject(s) - antibody dependent cell mediated cytotoxicity , chimeric antigen receptor , antibody , antigen , nk 92 , cytotoxic t cell , biology , interleukin 21 , cytotoxicity , cell culture , lymphokine activated killer cell , microbiology and biotechnology , interleukin 12 , janus kinase 3 , cancer research , immunotherapy , immunology , immune system , monoclonal antibody , cd8 , biochemistry , in vitro , genetics
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.