NK cells engineered to express a GD2‐specific antigen receptor display built‐in ADCC‐like activity against tumour cells of neuroectodermal origin

Journal of Cellular and Molecular Medicine

Ruth Esser¹  Tina Müller⁸  Dörthe Stefes⁸  Stephan Kloess¹  Diana Seidel⁷  Stephen D. Gillies⁵  Christel Aperlo-Iffland³  James S. Huston³  Christoph Uherek⁸  Kurt Schönfeld⁸  Torsten Tonn²  Nicole Huebener⁴  Holger N. Lode⁶  Ulrike Koehl¹ 

[1] Pediatric Hematology and Oncology, University Hospital, Frankfurt am Main, Germany;DRK-Blutspendedienst Ost and Center for Regenerative Therapies Dresden (CRTD), Medical Faculty Carl Gustav Carus, Technical University Dresden, Dresden, Germany;EMD Serono Research Institute, Inc., Billerica, MA, USA;TTUHSC, Department of Cell Biology and Biochemistry, Lubbock, TX, USA;Provenance Biopharmaceuticals Corp., Waltham, MA, USA;University Children’s Hospital, University of Greifswald, Greifswald, Germany;Department of Pediatrics, Charité University Medicine Berlin, Berlin, Germany;Chemotherapeutisches Forschungsinstitut Georg-Speyer-Haus, Frankfurt am Main, Germany

关键词: neuroblastoma;    natural killer cells;    chimeric antigen receptor;    GD2;    adoptive immunotherapy;   

DOI  :  10.1111/j.1582-4934.2011.01343.x

来源: Wiley

【 摘 要 】

Abstract

Treatment of high-risk neuroblastoma (NB) represents a major challenge in paediatric oncology. Alternative therapeutic strategies include antibodies targeting the disialoganglioside GD₂, 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 GD₂-specific chimeric antigen receptor (CAR) comprising an anti-GD₂ 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 GD₂ 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 GD₂-specific antibody or anti-idiotypic antibody occupying the CAR’s cell recognition domain. Importantly, strongly enhanced cytotoxicity of the GD₂-specific NK cells was also found against primary NB cells and GD₂ expressing tumour cells of other origins, demonstrating the potential clinical utility of the retargeted effector cells.

【 授权许可】

Unknown   
© 2011 The Authors Journal of Cellular and Molecular Medicine © 2011 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd