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 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.

DAP12-Based Activating Chimeric Antigen Receptor for NK Cell Tumor Immunotherapy

“…However, concern has been raised about genetically modified autoreactive T cells, which might cause undesirable side effects after infusion into patients. NK cells, in contrast, do not possess TCR-like molecules that might (21,(41)(42)(43)(65)(66)(67)(68).…”

“…3 were also incubated with the bladder carcinoma cell lines RT4 and HT1376, which show endogenous expression of PSCA. *p , 0.05. edge, we treated for the first time established solid tumors with CAR-modified NK cells, whereas other groups favored mixing of NK cells and target cells prior to tumor transplantation (23,(65)(66)(67) or chose an experimental setting that most likely confronts injected tumor cells and CAR-modified NK cells in the bloodstream or lung capillaries (67). In this article, we demonstrate that treatment with YTS anti-PSCA-DAP12 NK cells resulted in a significantly delayed growth of PSCA-positive tumors when compared with tumors treated with YTS wt cells and YTS myc-DAP12 controls, respectively.…”

NK cells and cancer: you can teach innate cells new tricks

“…142) and CD20 (REF. 143) expressed on B cell malignancies; disialoganglioside G D2 , a glycolipid expressed on neuroblastoma 144 and various other cancer types 145 ; HER2 (also known as ERBB2), an antigen expressed by tumours of epithelial origin [146][147][148] ; epithelial cell adhesion molecule (EPCAM), a molecule over expressed by carcinomas and cancer stem cells 149 ; HLA-A2 loaded with the mela noma antigen gp100 (also known as PMEL) 150 ; prostate stem cell antigen (PSCA) 151 ; and CD138 (also known as SYND1), which is expressed by multiple myeloma cells 152 . Because NK-92 cells are a tumour cell line infected with Epstein-Barr virus (EBV), they must be irradiated to prevent their proliferation before being adoptively transferred.…”

Infusions of Allogeneic Natural Killer Cells as Cancer Therapy

“…Investigations have shown that NK cells transduced with anti-CD19 CAR or NKG2D are potent against B-lineage and osteosarcoma cells in vivo and in vitro (49,52). CAR þ cells have been generated against GD2 in neuroblastoma and CD33/CD123 in myeloid leukemia (51,53,54 …”