Article
Generation and evaluation of a chimeric NK-cell receptor for an experimental immunotherapy of gliomas
Herstellung und Evaluierung eines chimären NK-Zell-Rezeptors zur experimentellen Immuntherapie von Gliomen
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Published: | May 30, 2008 |
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Objective: Natural killer (NK) cells represent 10-15% of circulating blood leukocytes and belong to the innate immune system. They are indispensable for defeating virus infected or transformed cells. Upon activation NK cells are capable of killing target cells by secretion of granzyme/perforin or the action of death ligands (i.e. TRAIL, Fas-L). The objective of the project was the construction and evaluation of a glioma-specific NK-cell receptor.
Methods: A new immunotherapeutic approach for the treatment of gliomas is the genetic modification of NK cells with chimeric NK-receptors consisting of single chain antibody fragments (scFv) fused to the signal-transducing NK-receptor subunits. As pilot antigen on glioma cells the “Prostate Stem Cell Antigen”, a newly identified glioma associated antigen, was chosen.
An established single antibody fragment against PSCA (scFv-AM1) was fused to DAP12 signal-transducing subunit of the CD94/NKG2C complex and evaluated in vitro.
Results: The scFv-DAP12 construct was efficiently transported to the cell surface in 293T cells and, when integrated in a lentiviral vector, was successfully transduceded in permanent human NK cell lines. Transduced NK cells were capable of destroying PSCA-positive glioma cells whereas PSCA-negative cells were not affected. In other control experiments an appropriate empty vector construct (IgKappa-DAP12-construct) was not able to elicit an NK cell response against PSCA-positive glioma cells and PSCA-negative cells, respectively.
Conclusions: These data support the idea of using modified NK cells for an experimental immunotherapy of gliomas. By further modifying the amount of inhibitory and activating NK-receptor subsets it might be possible to prevail over the glioma cell-mediated inhibitory HLA-E/NKG2A/B-signaling in order to avoid anergy of NK cells.