Selective inhibition of tumor growth by clonal NK cells expressing an ErbB2/HER2-specific chimeric antigen receptor
Natural killer (NK) cells are an important effector cell type for adoptive cancer immunotherapy. Similar to T cells, NK cells can be modified to express chimeric antigen receptors (CARs) to enhance antitumor activity, but experience with CAR-engineered NK cells and their clinical development is stil...
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| Main Authors: | , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
2015
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| In: |
Molecular therapy
Year: 2014, Volume: 23, Issue: 2, Pages: 330-338 |
| ISSN: | 1525-0024 |
| DOI: | 10.1038/mt.2014.219 |
| Online Access: | Verlag, kostenfrei, Volltext: http://dx.doi.org/10.1038/mt.2014.219
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| Author Notes: | Kurt Schönfeld, Christiane Sahm, Congcong Zhang, Sonja Naundorf, Christian Brendel, Marcus Odendahl, Paulina Nowakowska, Halvard Bönig, Ulrike Köhl, Stephan Kloess, Sylvia Köhler, Heidi Holtgreve-Grez, Anna Jauch, Manfred Schmidt, Ralf Schubert, Klaus Kühlcke, Erhard Seifried, Hans G. Klingemann, Michael A. Rieger, Torsten Tonn, Manuel Grez, Winfried S. Wels |
| Summary: | Natural killer (NK) cells are an important effector cell type for adoptive cancer immunotherapy. Similar to T cells, NK cells can be modified to express chimeric antigen receptors (CARs) to enhance antitumor activity, but experience with CAR-engineered NK cells and their clinical development is still limited. Here, we redirected continuously expanding and clinically usable established human NK-92 cells to the tumor-associated ErbB2 (HER2) antigen. Following GMP-compliant procedures, we generated a stable clonal cell line expressing a humanized CAR based on ErbB2-specific antibody FRP5 harboring CD28 and CD3ζ signaling domains (CAR 5.28.z). These NK-92/5.28.z cells efficiently lysed ErbB2-expressing tumor cells in vitro and exhibited serial target cell killing. Specific recognition of tumor cells and antitumor activity were retained in vivo, resulting in selective enrichment of NK-92/5.28.z cells in orthotopic breast carcinoma xenografts, and reduction of pulmonary metastasis in a renal cell carcinoma model, respectively. γ-irradiation as a potential safety measure for clinical application prevented NK cell replication, while antitumor activity was preserved. Our data demonstrate that it is feasible to engineer CAR-expressing NK cells as a clonal, molecularly and functionally well-defined and continuously expandable cell therapeutic agent, and suggest NK-92/5.28.z cells as a promising candidate for use in adoptive cancer immunotherapy. |
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| Item Description: | Published online: 9 December 2014 Gesehen am 28.04.2017 |
| Physical Description: | Online Resource |
| ISSN: | 1525-0024 |
| DOI: | 10.1038/mt.2014.219 |