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

作者：Esser Ruth; Mueller Tina; Stefes Doerthe; Kloess Stephan; Seidel Diana; Gillies Stephen D; Aperlo Iffland Christel; Huston James S; Uherek Christoph; Schoenfeld Kurt; Tonn Torsten; Huebener Nicole; Lode Holger N; Koehl Ulrike; Wels Winfried S^*

来源：JOURNAL OF CELLULAR AND MOLECULAR MEDICINE, 2012, 16(3): 569-581.

DOI：10.1111/j.1582-4934.2011.01343.x

• neuroblastoma
• natural killer cells
• chimeric antigen receptor
• GD2
• adoptive immunotherapy

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-? 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 CARs 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.

• 出版日期2012-3