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Blood, 15 August 2002, Vol. 100, No. 4, pp. 1265-1273
GENE THERAPY
Retargeting of natural killer-cell cytolytic activity to
ErbB2-expressing cancer cells results in efficient and selective tumor
cell destruction
Christoph Uherek,
Torsten Tonn,
Barbara Uherek,
Sven Becker,
Barbara Schnierle,
Hans-Georg Klingemann, and
Winfried Wels
From the Chemotherapeutisches Forschungsinstitut
Georg-Speyer-Haus, Frankfurt am Main, Germany; Institute for
Transfusion Medicine and Immunohematology Red Cross Blood Donor Service
(RCBDS), Frankfurt am Main, Germany; and Section of Bone Marrow
Transplant and Cell Therapy, Rush Medical College, Chicago, IL.
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  chain.
Transduced NK-92-scFv(FRP5)- 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)-
cells toward ErbB2-negative targets was found. However, even at low
effector-to-target ratios, NK-92-scFv(FRP5)- 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.
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