Retargeting of natural killer-cell cytolytic activity to ErbB2-expressing cancer cells results in efficient and selective tumor cell destruction.
The continuously growing natural killer (NK) cell line NK-92 is highly cytotoxic against malignant cells of various origins without affecting normal human cells. Based on this selectivity, the potential of NK-92 cells for adoptive therapy is currently being investigated in phase I clinical studies. To further enhance the antitumoral activity of NK-92 cells and expand the range of tumor entities suitable for NK-92-based therapies, here by transduction with a retroviral vector we have generated genetically modified NK-92 cells expressing a chimeric antigen receptor specific for the tumor-associated ErbB2 (HER2/neu) antigen, which is overexpressed by many tumors of epithelial origin. The chimeric antigen receptor consists of the ErbB2-specific scFv(FRP5) antibody fragment, a flexible hinge region derived from CD8, and transmembrane and intracellular regions of the CD3 zeta chain. Transduced NK-92-scFv(FRP5)-zeta cells express high levels of the fusion protein on the cell surface as determined by fluorescence-activated cell-scanning (FACS) analysis. In europium release assays, no difference in cytotoxic activity of NK-92 and NK-92-scFv(FRP5)-zeta cells toward ErbB2-negative targets was found. However, even at low effector-to-target ratios, NK-92-scFv(FRP5)-zeta cells specifically and efficiently lysed established and primary ErbB2-expressing tumor cells that were completely resistant to cytolytic activity of parental NK-92 cells. These results demonstrate that efficient retargeting of NK-92 cytotoxicity can be achieved and might allow the generation of potent cell-based therapeutics for the treatment of ErbB2-expressing malignancies.
Uherek
Christoph
C
Chemotherapeutisches Forschungsinstitut Georg-Speyer-Haus, Frankfurt am Main, Germany.
Tonn
Torsten
T
Uherek
Barbara
B
Becker
Sven
S
Schnierle
Barbara
B
Klingemann
Hans-Georg
HG
Wels
Winfried
W
D017209:Apoptosis; D001943:Breast Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy; D017252:CD3 Complex / Q000235:genetics; D016827:CD8 Antigens / Q000235:genetics; D002455:Cell Division; D002460:Cell Line; D003602:Cytotoxicity, Immunologic; D005434:Flow Cytometry; D006801:Humans; D007135:Immunoglobulin Variable Region / Q000235:genetics; D016219:Immunotherapy, Adoptive; D020287:In Situ Nick-End Labeling; D007694:Killer Cells, Natural / Q000276:immunology*; D009369:Neoplasms / Q000276:immunology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis / Q000235:genetics / Q000276:immunology*; D011946:Receptors, Antigen / Q000235:genetics; D011993:Recombinant Fusion Proteins; D014407:Tumor Cells, Cultured
D017252:CD3 Complex; D016827:CD8 Antigens; D007135:Immunoglobulin Variable Region; D018719:Erb-b2 Receptor Tyrosine Kinases; D011946:Receptors, Antigen; D011993:Recombinant Fusion Proteins