title: Expression of a CD20-specific chimeric antigen receptor enhances cytotoxic activity of NK cells and overcomes NK-resistance of lymphoma and leukemia cells.
abstract: Despite the clinical success of CD20-specific antibody rituximab, malignancies of B-cell origin continue to present a major clinical challenge, in part due to an inability of the antibody to activate antibody-dependent cell-mediated cytotoxicity (ADCC) in some patients, and development of resistance in others. Expression of chimeric antigen receptors in effector cells operative in ADCC might allow to bypass insufficient activation via FcgammaRIII and other resistance mechanisms that limit natural killer (NK)-cell activity. Here we have generated genetically modified NK cells carrying a chimeric antigen receptor that consists of a CD20-specific scFv antibody fragment, via a flexible hinge region connected to the CD3zeta chain as a signaling moiety. As effector cells we employed continuously growing, clinically applicable human NK-92 cells. While activity of the retargeted NK-92 against CD20-negative targets remained unchanged, the gene modified NK cells displayed markedly enhanced cytotoxicity toward NK-sensitive CD20 expressing cells. Importantly, in contrast to parental NK-92, CD20-specific NK cells efficiently lysed CD20 expressing but otherwise NK-resistant established and primary lymphoma and leukemia cells, demonstrating that this strategy can overcome NK-cell resistance and might be suitable for the development of effective cell-based therapeutics for the treatment of B-cell malignancies.
authors: Chemotherapeutisches Forschungsinstitut Georg-Speyer-Haus, Paul-Ehrlich-Strasse 42-44, 60596 Frankfurt am Main, Germany.
authors: Tina
authors: T
authors: Müller
authors: Christoph
authors: C
authors: Uherek
authors: Guitta
authors: G
authors: Maki
authors: Kai Uwe
authors: KU
authors: Chow
authors: Annemarie
authors: A
authors: Schimpf
authors: Hans-Georg
authors: HG
authors: Klingemann
authors: Torsten
authors: T
authors: Tonn
authors: Winfried S
authors: WS
authors: Wels
mesh_terms: D000818:Animals; D018951:Antigens, CD20 / Q000276:immunology*; D049109:Cell Proliferation; D003602:Cytotoxicity, Immunologic / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007135:Immunoglobulin Variable Region / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology*; D007700:Kinetics; D007938:Leukemia / Q000276:immunology* / Q000473:pathology; D008223:Lymphoma / Q000276:immunology* / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D041681:NIH 3T3 Cells; D011947:Receptors, Antigen, B-Cell / Q000096:biosynthesis* / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D014407:Tumor Cells, Cultured
chemical_list: D018951:Antigens, CD20; D007135:Immunoglobulin Variable Region; D011947:Receptors, Antigen, B-Cell; D011993:Recombinant Fusion Proteins
references: Clin Cancer Res. 1996 Jun;2(6):1001-8
references: 9816261
references: Biol Blood Marrow Transplant. 1996 May;2(2):68-75
references: 9118301
references: Haematologica. 2002 Jan;87(1):33-43
references: 11801463
references: Nat Rev Immunol. 2005 Dec;5(12):928-40
references: 16322746
references: Blood. 2000 May 15;95(10):3052-6
references: 10807768
references: Exp Hematol. 2005 Mar;33(3):344-52
references: 15730858
references: Proc Natl Acad Sci U S A. 1994 May 10;91(10):4318-22
references: 7910405
references: Oncogene. 2005 Mar 24;24(13):2121-43
references: 15789036
references: Blood. 2001 Jan 1;97(1):101-6
references: 11133748
references: J Virol Methods. 1999 Aug;81(1-2):71-5
references: 10488763
references: Semin Cancer Biol. 2003 Jun;13(3):211-22
references: 12959352
references: Blood. 1994 Oct 15;84(8):2457-66
references: 7522629
references: Immunobiology. 1989 Jun;179(2-3):230-43
references: 2793204
references: Clin Cancer Res. 2000 Nov;6(11):4314-22
references: 11106249
references: Blood. 2003 Mar 15;101(6):2099-114
references: 12511419
references: Science. 1997 Jun 13;276(5319):1719-24
references: 9180086
references: Protein Eng. 2001 Dec;14(12):1025-33
references: 11809933
references: Nucleic Acids Res. 1991 Aug 11;19(15):4133-7
references: 1908075
references: Biochem Biophys Res Commun. 1998 Nov 18;252(2):368-72
references: 9826536
references: J Clin Oncol. 2000 Sep;18(17):3135-43
references: 10963642
references: J Clin Oncol. 2003 Nov 1;21(21):3940-7
references: 12975461
references: J Immunother (1991). 1991 Oct;10(5):336-46
references: 1790141
references: Curr Top Microbiol Immunol. 1998;230:221-44
references: 9586358
references: Blood. 2002 Sep 15;100(6):1935-47
references: 12200350
references: Chem Biol. 2005 May;12(5):567-77
references: 15911377
references: Blood. 2002 Feb 1;99(3):754-8
references: 11806974
references: J Hematother Stem Cell Res. 2001 Aug;10(4):535-44
references: 11522236
references: Blood. 2004 Nov 1;104(9):2635-42
references: 15226177
references: J Clin Oncol. 2005 Sep 10;23(26):6421-8
references: 16155029
references: Blood. 1997 Sep 15;90(6):2188-95
references: 9310469
references: Blood. 2005 Jul 1;106(1):376-83
references: 15755898
references: Eur Radiol. 2005 Jan;15(1):4-13
references: 15616814
references: Immunity. 1996 Jan;4(1):77-85
references: 8574854
references: Curr Top Microbiol Immunol. 2001;260:271-300
references: 11443878
references: Nat Rev Cancer. 2002 Nov;2(11):850-61
references: 12415255
references: Leukemia. 1994 Apr;8(4):652-8
references: 8152260
references: J Hematother. 1999 Jun;8(3):281-90
references: 10417052
references: Clin Cancer Res. 1998 Nov;4(11):2859-68
references: 9829753
references: J Clin Oncol. 2001 Jan 15;19(2):389-97
references: 11208830
references: Gene Ther. 2003 Jul;10(14):1189-97
references: 12833128
references: Mol Cell Biol. 1985 Dec;5(12):3610-6
references: 3915782
references: Cell Death Differ. 2006 Apr;13(4):576-85
references: 16179940
references: Blood. 2002 Aug 15;100(4):1265-73
references: 12149207
references: Trends Immunol. 2002 May;23(5):240-5
references: 12102744
references: J Hematother Stem Cell Res. 2001 Aug;10(4):523-34
references: 11522235
references: J Clin Oncol. 1998 Aug;16(8):2825-33
references: 9704735
references: Annu Rev Immunol. 2001;19:197-223
references: 11244035
references: J Immunol. 1995 Jul 15;155(2):1000-9
references: 7608531