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

J Cell Mol Med. 2012 Mar;16(3):569-81. doi: 10.1111/j.1582-4934.2011.01343.x.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies, Monoclonal / genetics
  • Antibodies, Monoclonal / immunology
  • Antibody-Dependent Cell Cytotoxicity / immunology*
  • CD3 Complex / genetics
  • CD3 Complex / immunology
  • Cell Line, Tumor
  • Child
  • Gangliosides / genetics
  • Gangliosides / immunology
  • Gene Expression
  • Genetic Engineering
  • Genetic Vectors
  • Humans
  • Immunotherapy, Adoptive
  • Jejunal Neoplasms / immunology
  • Jejunal Neoplasms / secondary
  • Jejunal Neoplasms / therapy*
  • Jejunum / immunology
  • Jejunum / pathology
  • Killer Cells, Natural / cytology
  • Killer Cells, Natural / immunology
  • Killer Cells, Natural / metabolism*
  • Neuroblastoma / immunology
  • Neuroblastoma / secondary
  • Neuroblastoma / therapy*
  • Receptors, Antigen / genetics
  • Receptors, Antigen / immunology
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / immunology
  • Retroviridae
  • Transduction, Genetic


  • Antibodies, Monoclonal
  • CD3 Complex
  • Gangliosides
  • Receptors, Antigen
  • Recombinant Fusion Proteins
  • ganglioside, GD2
  • dinutuximab