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Mol Ther. 2015 Feb;23(2):330-8. doi: 10.1038/mt.2014.219. Epub 2014 Nov 6.

Selective inhibition of tumor growth by clonal NK cells expressing an ErbB2/HER2-specific chimeric antigen receptor.

Author information

1
Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt am Main, Germany.
2
EUFETS GmbH, Idar-Oberstein, Germany.
3
Institute for Transfusion Medicine, German Red Cross Blood Donation Service North-East, Dresden and Transfusion Medicine, Medical Faculty Carl Gustav Carus, TU Dresden, Dresden, Germany.
4
Institute for Transfusion Medicine and Immunohematology, Goethe University, and German Red Cross Blood Donation Service Baden-Württemberg-Hessen, Frankfurt am Main, Germany.
5
Institute of Cellular Therapeutics, Hannover Medical School, Hannover, Germany.
6
Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany.
7
Department of Translational Oncology, National Center for Tumor Diseases and German Cancer Research Center, Heidelberg, Germany.
8
Pediatric Pulmonology, Allergy and Cystic Fibrosis, University Hospital, Frankfurt am Main, Germany.
9
Conkwest Inc., Cardiff-by-the-Sea, California, USA.
10
1] Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt am Main, Germany [2] Department of Hematology/Oncology, University Hospital, Frankfurt am Main, Germany [3] German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
11
1] Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt am Main, Germany [2] German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany.

Abstract

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.

PMID:
25373520
PMCID:
PMC4445620
DOI:
10.1038/mt.2014.219
[Indexed for MEDLINE]
Free PMC Article

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