title: Analysis of cytotoxic T lymphocytes from a patient with hepatocellular carcinoma who showed a clinical response to vaccination with a glypican‑3‑derived peptide.
abstract: Glypican-3 (GPC3), which is a carcinoembryonic antigen, is overexpressed in human hepatocellular carcinoma (HCC). Previously, we performed a phase I clinical trial of GPC3‑derived peptide vaccination in patients with advanced HCC, and reported that GPC3 peptide vaccination is safe and has clinical efficacy. Moreover, we proposed that a peptide‑specific CTL response is a predictive marker of overall survival in patients with HCC who receive peptide vaccination. In this study, we established GPC3‑derived peptide-specific CTL clones from the PBMCs of an HLA-A*02:07-positive patient with HCC who was vaccinated with an HLA-A2-restricted GPC3 peptide vaccine and showed a clinical response in the phase I clinical trial. Established CTL clones were analyzed using the IFN-γ ELISPOT assay and a cytotoxicity assay. GPC3 peptide-specific CTL clones were established successfully from the PBMCs of the patient. One CTL clone showed cytotoxicity against cancer cell lines that expressed endogenously the GPC3 peptide. The results suggest that CTLs have high avidity, and that natural antigen-specific killing activity against tumor cells can be induced in a patient with HCC who shows a clinical response to vaccination with the GPC3144-152 peptide.
authors.affiliation: Division of Cancer Immunotherapy, Research Center for Innovative Oncology, National Cancer Center Hospital East, Kashiwa, Chiba 277‑8577, Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Tada
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Yoshikawa
authors.forename: Manami
authors.initials: M
authors.lastname: Shimomura
authors.forename: Yu
authors.initials: Y
authors.lastname: Sawada
authors.forename: Mayuko
authors.initials: M
authors.lastname: Sakai
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Shirakawa
authors.forename: Daisuke
authors.initials: D
authors.lastname: Nobuoka
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Nakatsura
mesh_terms: D019496:Cancer Vaccines / Q000008:administration & dosage / Q000276:immunology; D006528:Carcinoma, Hepatocellular / Q000097:blood / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D017321:Clinical Trials, Phase I as Topic; D005260:Female; D053673:Glypicans / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D015789:HLA-A2 Antigen / Q000235:genetics / Q000276:immunology; D006801:Humans; D008113:Liver Neoplasms / Q000097:blood / Q000276:immunology / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D008297:Male; D010455:Peptides / Q000008:administration & dosage* / Q000276:immunology / Q000627:therapeutic use; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014611:Vaccination
chemical_list: D019496:Cancer Vaccines; D053673:Glypicans; C524866:HLA-A*02 antigen; D015789:HLA-A2 Antigen; D010455:Peptides
references.citation: Oncoimmunology. 2012 Nov 1;1(8):1448-1450
references.pmid: 23243625
references.citation: J Immunol. 1996 May 15;156(10):3882-91
references.pmid: 8621927
references.citation: Hum Vaccin Immunother. 2013 Jan;9(1):210-2
references.pmid: 23442593
references.citation: J Immunol. 2000 Jul 1;165(1):533-8
references.pmid: 10861093
references.citation: Eur J Immunol. 2013 Apr;43(4):1109-20
references.pmid: 23280567
references.citation: CA Cancer J Clin. 2011 Mar-Apr;61(2):69-90
references.pmid: 21296855
references.citation: Hum Immunol. 1997 Nov;58(1):12-20
references.pmid: 9438205
references.citation: Immunol Today. 1996 Jun;17(6):261-6
references.pmid: 8962628
references.citation: Int J Cancer. 2010 Dec 15;127(12):2893-917
references.pmid: 21351269
references.citation: Int J Oncol. 2011 Oct;39(4):1041-9
references.pmid: 21687943
references.citation: Transfusion. 1996 Sep;36(9):818-21
references.pmid: 8823458
references.citation: J Mol Biol. 1991 May 20;219(2):277-319
references.pmid: 2038058
references.citation: Biochem Biophys Res Commun. 2003 Jun 20;306(1):16-25
references.pmid: 12788060
references.citation: Di Yi Jun Yi Da Xue Xue Bao. 2005 Mar;25(3):321-4
references.pmid: 15772003
references.citation: J Immunol. 2004 Dec 15;173(12):7622-9
references.pmid: 15585890
references.citation: N Engl J Med. 2008 Jul 24;359(4):378-90
references.pmid: 18650514
references.citation: Acta Virol. 2011;55(2):107-15
references.pmid: 21692558
references.citation: Hum Immunol. 2000 Mar;61(3):334-40
references.pmid: 10689125
references.citation: Hepat Mon. 2012 Oct;12(10 HCC):e6894
references.pmid: 23233864
references.citation: Tissue Antigens. 2001 Jun;57(6):502-7
references.pmid: 11556980
references.citation: Lancet Oncol. 2009 Jan;10(1):25-34
references.pmid: 19095497
references.citation: Gastroenterology. 2003 Jul;125(1):89-97
references.pmid: 12851874
references.citation: J Transl Med. 2005 Sep 20;3:35
references.pmid: 16174302
references.citation: Hepatol Res. 2011 Apr;41(4):296-302
references.pmid: 21348907
references.citation: Mol Cancer Ther. 2007 Jul;6(7):2081-91
references.pmid: 17620437
references.citation: Cancer Res. 2006 Feb 15;66(4):2414-22
references.pmid: 16489048
references.citation: Am J Hum Genet. 1976 Jul;28(4):390-9
references.pmid: 941906
references.citation: Cancer Sci. 2009 Aug;100(8):1403-7
references.pmid: 19496787
references.citation: Hum Vaccin Immunother. 2013 Jun;9(6):1228-33
references.pmid: 23466818
references.citation: Clin Cancer Res. 2004 Dec 15;10(24):8630-40
references.pmid: 15623647
references.citation: Dig Dis. 2011;29(3):303-9
references.pmid: 21829021
references.citation: BioDrugs. 2005;19(2):71-7
references.pmid: 15807627
references.citation: Tissue Antigens. 1995 Apr;45(4):223-31
references.pmid: 7638857
references.citation: J Hepatol. 2006 Dec;45(6):868-78
references.pmid: 17046096
references.citation: Hepatology. 2011 Apr;53(4):1206-16
references.pmid: 21480325
references.citation: Cancer Res. 2001 Mar 1;61(5):2038-46
references.pmid: 11280764
references.citation: Clin Cancer Res. 2012 Jul 1;18(13):3686-96
references.pmid: 22577059
references.citation: Immunol Res. 2012 Sep;53(1-3):182-90
references.pmid: 22434516
references.citation: Clin Cancer Res. 2006 May 1;12(9):2689-97
references.pmid: 16675560
references.citation: Biochem J. 1995 Oct 15;311 ( Pt 2):561-5
references.pmid: 7487896
references.citation: Cancer Sci. 2012 Mar;103(3):408-14
references.pmid: 22126448
references.citation: Cancer Sci. 2011 May;102(5):918-25
references.pmid: 21281401
references.citation: J Immunol. 2002 Oct 1;169(7):4017-24
references.pmid: 12244204
references.citation: Tissue Antigens. 2002 Oct;60(4):319-27
references.pmid: 12472661
references.citation: Cell. 1993 Nov 19;75(4):693-708
references.pmid: 7694806
references.citation: Int J Oncol. 2013 Mar;42(3):831-8
references.pmid: 23354275
references.citation: Dig Dis Sci. 2013 Mar;58(3):759-67
references.pmid: 23053887
references.citation: Int J Oncol. 2008 May;32(5):985-90
references.pmid: 18425324
references.citation: Int J Oncol. 2009 Mar;34(3):649-56
references.pmid: 19212669
references.citation: Curr Opin Immunol. 1998 Aug;10(4):478-82
references.pmid: 9722926
references.citation: Anticancer Res. 2009 Feb;29(2):647-55
references.pmid: 19331215
references.citation: Cancer Sci. 2010 Mar;101(3):594-600
references.pmid: 20132220
references.citation: J Clin Invest. 2001 Aug;108(4):497-501
references.pmid: 11518720