title: ErbB2/HER2-Specific NK Cells for Targeted Therapy of Glioblastoma.
abstract: BACKGROUND
  Glioblastoma (GBM) is the most common and malignant intracranial tumor in adults and currently incurable. To specifically target natural killer (NK) cell activity to GBM, we employed NK-92/5.28.z cells that are continuously expanding human NK cells expressing an ErbB2-specific chimeric antigen receptor (CAR).
  
  
  METHODS
  ErbB2 expression in 56 primary tumors, four primary cell cultures, and seven established cell lines was assessed by immunohistochemistry and flow cytometry. Cell killing activity of NK-92/5.28.z cells was analyzed in in vitro cytotoxicity assays. In vivo antitumor activity was evaluated in NOD-SCID IL2Rγ(null) (NSG) mice carrying orthotopic human GBM xenografts (6 to 11 mice per group) and C57BL/6 mice carrying subcutaneous and orthotopic ErbB2-expressing murine GBM tumors (5 to 8 mice per group). Statistical tests were two-sided.
  
  
  RESULTS
  We found elevated ErbB2 protein expression in 41% of primary GBM samples and in the majority of GBM cell lines investigated. In in vitro assays, NK-92/5.28.z in contrast to untargeted NK-92 cells lysed all ErbB2-positive established and primary GBM cells analyzed. Potent in vivo antitumor activity of NK-92/5.28.z was observed in orthotopic GBM xenograft models in NSG mice, leading to a marked extension of symptom-free survival upon repeated stereotactic injection of CAR NK cells into the tumor area (median survival of 200.5 days upon treatment with NK-92/5.28.z vs 73 days upon treatment with parental NK-92 cells, P < .001). In immunocompetent mice, local therapy with NK-92/5.28.z cells resulted in cures of transplanted syngeneic GBM in four of five mice carrying subcutaneous tumors and five of eight mice carrying intracranial tumors, induction of endogenous antitumor immunity, and long-term protection against tumor rechallenge at distant sites.
  
  
  CONCLUSIONS
  Our data demonstrate the potential of ErbB2-specific NK-92/5.28.z cells for adoptive immunotherapy of glioblastoma, justifying evaluation of this approach for the treatment of ErbB2-positive GBM in clinical studies.
authors.affiliation: Affiliations of authors:Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt am Main , Germany (CZ, SG, KS, WSW); German Cancer Consortium (DKTK), partner site Frankfurt/Mainz , Germany (CZ, MCB, JPS, WSW); German Cancer Research Center (DKFZ), Heidelberg , Germany (CZ, MCB); Institute for Neurooncology (MCB, JPS), Edinger Institute (LJ, PZ, PNH, MM), Department of Neurology (PZ), and Institute of Neuroradiology (EH), Goethe University, Frankfurt am Main , Germany ; Institute for Transfusion Medicine, German Red Cross Blood Donation Service North-East and Medical Faculty Carl Gustav Carus, TU Dresden , Dresden , Germany (TT).
authors.forename: Congcong
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Affiliations of authors:Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt am Main , Germany (CZ, SG, KS, WSW); German Cancer Consortium (DKTK), partner site Frankfurt/Mainz , Germany (CZ, MCB, JPS, WSW); German Cancer Research Center (DKFZ), Heidelberg , Germany (CZ, MCB); Institute for Neurooncology (MCB, JPS), Edinger Institute (LJ, PZ, PNH, MM), Department of Neurology (PZ), and Institute of Neuroradiology (EH), Goethe University, Frankfurt am Main , Germany ; Institute for Transfusion Medicine, German Red Cross Blood Donation Service North-East and Medical Faculty Carl Gustav Carus, TU Dresden , Dresden , Germany (TT).
authors.forename: Michael C
authors.initials: MC
authors.lastname: Burger
authors.affiliation: Affiliations of authors:Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt am Main , Germany (CZ, SG, KS, WSW); German Cancer Consortium (DKTK), partner site Frankfurt/Mainz , Germany (CZ, MCB, JPS, WSW); German Cancer Research Center (DKFZ), Heidelberg , Germany (CZ, MCB); Institute for Neurooncology (MCB, JPS), Edinger Institute (LJ, PZ, PNH, MM), Department of Neurology (PZ), and Institute of Neuroradiology (EH), Goethe University, Frankfurt am Main , Germany ; Institute for Transfusion Medicine, German Red Cross Blood Donation Service North-East and Medical Faculty Carl Gustav Carus, TU Dresden , Dresden , Germany (TT).
authors.forename: Lukas
authors.initials: L
authors.lastname: Jennewein
authors.affiliation: Affiliations of authors:Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt am Main , Germany (CZ, SG, KS, WSW); German Cancer Consortium (DKTK), partner site Frankfurt/Mainz , Germany (CZ, MCB, JPS, WSW); German Cancer Research Center (DKFZ), Heidelberg , Germany (CZ, MCB); Institute for Neurooncology (MCB, JPS), Edinger Institute (LJ, PZ, PNH, MM), Department of Neurology (PZ), and Institute of Neuroradiology (EH), Goethe University, Frankfurt am Main , Germany ; Institute for Transfusion Medicine, German Red Cross Blood Donation Service North-East and Medical Faculty Carl Gustav Carus, TU Dresden , Dresden , Germany (TT).
authors.forename: Sabrina
authors.initials: S
authors.lastname: Genßler
authors.affiliation: Affiliations of authors:Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt am Main , Germany (CZ, SG, KS, WSW); German Cancer Consortium (DKTK), partner site Frankfurt/Mainz , Germany (CZ, MCB, JPS, WSW); German Cancer Research Center (DKFZ), Heidelberg , Germany (CZ, MCB); Institute for Neurooncology (MCB, JPS), Edinger Institute (LJ, PZ, PNH, MM), Department of Neurology (PZ), and Institute of Neuroradiology (EH), Goethe University, Frankfurt am Main , Germany ; Institute for Transfusion Medicine, German Red Cross Blood Donation Service North-East and Medical Faculty Carl Gustav Carus, TU Dresden , Dresden , Germany (TT).
authors.forename: Kurt
authors.initials: K
authors.lastname: Schönfeld
authors.affiliation: Affiliations of authors:Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt am Main , Germany (CZ, SG, KS, WSW); German Cancer Consortium (DKTK), partner site Frankfurt/Mainz , Germany (CZ, MCB, JPS, WSW); German Cancer Research Center (DKFZ), Heidelberg , Germany (CZ, MCB); Institute for Neurooncology (MCB, JPS), Edinger Institute (LJ, PZ, PNH, MM), Department of Neurology (PZ), and Institute of Neuroradiology (EH), Goethe University, Frankfurt am Main , Germany ; Institute for Transfusion Medicine, German Red Cross Blood Donation Service North-East and Medical Faculty Carl Gustav Carus, TU Dresden , Dresden , Germany (TT).
authors.forename: Pia
authors.initials: P
authors.lastname: Zeiner
authors.affiliation: Affiliations of authors:Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt am Main , Germany (CZ, SG, KS, WSW); German Cancer Consortium (DKTK), partner site Frankfurt/Mainz , Germany (CZ, MCB, JPS, WSW); German Cancer Research Center (DKFZ), Heidelberg , Germany (CZ, MCB); Institute for Neurooncology (MCB, JPS), Edinger Institute (LJ, PZ, PNH, MM), Department of Neurology (PZ), and Institute of Neuroradiology (EH), Goethe University, Frankfurt am Main , Germany ; Institute for Transfusion Medicine, German Red Cross Blood Donation Service North-East and Medical Faculty Carl Gustav Carus, TU Dresden , Dresden , Germany (TT).
authors.forename: Elke
authors.initials: E
authors.lastname: Hattingen
authors.affiliation: Affiliations of authors:Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt am Main , Germany (CZ, SG, KS, WSW); German Cancer Consortium (DKTK), partner site Frankfurt/Mainz , Germany (CZ, MCB, JPS, WSW); German Cancer Research Center (DKFZ), Heidelberg , Germany (CZ, MCB); Institute for Neurooncology (MCB, JPS), Edinger Institute (LJ, PZ, PNH, MM), Department of Neurology (PZ), and Institute of Neuroradiology (EH), Goethe University, Frankfurt am Main , Germany ; Institute for Transfusion Medicine, German Red Cross Blood Donation Service North-East and Medical Faculty Carl Gustav Carus, TU Dresden , Dresden , Germany (TT).
authors.forename: Patrick N
authors.initials: PN
authors.lastname: Harter
authors.affiliation: Affiliations of authors:Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt am Main , Germany (CZ, SG, KS, WSW); German Cancer Consortium (DKTK), partner site Frankfurt/Mainz , Germany (CZ, MCB, JPS, WSW); German Cancer Research Center (DKFZ), Heidelberg , Germany (CZ, MCB); Institute for Neurooncology (MCB, JPS), Edinger Institute (LJ, PZ, PNH, MM), Department of Neurology (PZ), and Institute of Neuroradiology (EH), Goethe University, Frankfurt am Main , Germany ; Institute for Transfusion Medicine, German Red Cross Blood Donation Service North-East and Medical Faculty Carl Gustav Carus, TU Dresden , Dresden , Germany (TT).
authors.forename: Michel
authors.initials: M
authors.lastname: Mittelbronn
authors.affiliation: Affiliations of authors:Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt am Main , Germany (CZ, SG, KS, WSW); German Cancer Consortium (DKTK), partner site Frankfurt/Mainz , Germany (CZ, MCB, JPS, WSW); German Cancer Research Center (DKFZ), Heidelberg , Germany (CZ, MCB); Institute for Neurooncology (MCB, JPS), Edinger Institute (LJ, PZ, PNH, MM), Department of Neurology (PZ), and Institute of Neuroradiology (EH), Goethe University, Frankfurt am Main , Germany ; Institute for Transfusion Medicine, German Red Cross Blood Donation Service North-East and Medical Faculty Carl Gustav Carus, TU Dresden , Dresden , Germany (TT).
authors.forename: Torsten
authors.initials: T
authors.lastname: Tonn
authors.affiliation: Affiliations of authors:Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt am Main , Germany (CZ, SG, KS, WSW); German Cancer Consortium (DKTK), partner site Frankfurt/Mainz , Germany (CZ, MCB, JPS, WSW); German Cancer Research Center (DKFZ), Heidelberg , Germany (CZ, MCB); Institute for Neurooncology (MCB, JPS), Edinger Institute (LJ, PZ, PNH, MM), Department of Neurology (PZ), and Institute of Neuroradiology (EH), Goethe University, Frankfurt am Main , Germany ; Institute for Transfusion Medicine, German Red Cross Blood Donation Service North-East and Medical Faculty Carl Gustav Carus, TU Dresden , Dresden , Germany (TT).
authors.forename: Joachim P
authors.initials: JP
authors.lastname: Steinbach
authors.affiliation: Affiliations of authors:Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt am Main , Germany (CZ, SG, KS, WSW); German Cancer Consortium (DKTK), partner site Frankfurt/Mainz , Germany (CZ, MCB, JPS, WSW); German Cancer Research Center (DKFZ), Heidelberg , Germany (CZ, MCB); Institute for Neurooncology (MCB, JPS), Edinger Institute (LJ, PZ, PNH, MM), Department of Neurology (PZ), and Institute of Neuroradiology (EH), Goethe University, Frankfurt am Main , Germany ; Institute for Transfusion Medicine, German Red Cross Blood Donation Service North-East and Medical Faculty Carl Gustav Carus, TU Dresden , Dresden , Germany (TT).
authors.forename: Winfried S
authors.initials: WS
authors.lastname: Wels
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000276:immunology / Q000628:therapy*; D045744:Cell Line, Tumor; D005260:Female; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000276:immunology / Q000628:therapy*; D006801:Humans; D007150:Immunohistochemistry; D016219:Immunotherapy, Adoptive / Q000379:methods*; D007694:Killer Cells, Natural / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D058990:Molecular Targeted Therapy / Q000379:methods*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D018719:Erb-b2 Receptor Tyrosine Kinases; D011948:Receptors, Antigen, T-Cell; C508053:ERBB2 protein, human