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 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.
Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt am Main, Germany.
Kurt
K
Schönfeld
Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt am Main, Germany.
Christiane
C
Sahm
Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt am Main, Germany.
Congcong
C
Zhang
EUFETS GmbH, Idar-Oberstein, Germany.
Sonja
S
Naundorf
Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt am Main, Germany.
Christian
C
Brendel
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.
Marcus
M
Odendahl
Institute for Transfusion Medicine and Immunohematology, Goethe University, and German Red Cross Blood Donation Service Baden-Württemberg-Hessen, Frankfurt am Main, Germany.
Paulina
P
Nowakowska
Institute for Transfusion Medicine and Immunohematology, Goethe University, and German Red Cross Blood Donation Service Baden-Württemberg-Hessen, Frankfurt am Main, Germany.
Halvard
H
Bönig
Institute of Cellular Therapeutics, Hannover Medical School, Hannover, Germany.
Ulrike
U
Köhl
Institute of Cellular Therapeutics, Hannover Medical School, Hannover, Germany.
Stephan
S
Kloess
Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt am Main, Germany.
Sylvia
S
Köhler
Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany.
Heidi
H
Holtgreve-Grez
Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany.
Anna
A
Jauch
Department of Translational Oncology, National Center for Tumor Diseases and German Cancer Research Center, Heidelberg, Germany.
Manfred
M
Schmidt
Pediatric Pulmonology, Allergy and Cystic Fibrosis, University Hospital, Frankfurt am Main, Germany.
Ralf
R
Schubert
EUFETS GmbH, Idar-Oberstein, Germany.
Klaus
K
Kühlcke
Institute for Transfusion Medicine and Immunohematology, Goethe University, and German Red Cross Blood Donation Service Baden-Württemberg-Hessen, Frankfurt am Main, Germany.
Erhard
E
Seifried
Conkwest Inc., Cardiff-by-the-Sea, California, USA.
Hans G
HG
Klingemann
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.
Michael A
MA
Rieger
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.
Torsten
T
Tonn
Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt am Main, Germany.
Manuel
M
Grez
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.
Winfried S
WS
Wels
D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000276:immunology / Q000628:therapy; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D060965:Clonal Evolution; D003602:Cytotoxicity, Immunologic; D004195:Disease Models, Animal; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D015870:Gene Expression; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D016130:Immunophenotyping; D007167:Immunotherapy; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism*; D016086:Lentivirus / Q000235:genetics; D007959:Lymphocyte Culture Test, Mixed; D009369:Neoplasms / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy; D010641:Phenotype; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology*; D011971:Receptors, Immunologic / Q000235:genetics* / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000235:genetics*; D014161:Transduction, Genetic; D023041:Xenograft Model Antitumor Assays
D018984:Epitopes, T-Lymphocyte; D018719:Erb-b2 Receptor Tyrosine Kinases; D011971:Receptors, Immunologic; D011993:Recombinant Fusion Proteins