HLA-A2-restricted glypican-3 peptide-specific CTL clones induced by peptide vaccine show high avidity and antigen-specific killing activity against tumor cells

Toshiaki Yoshikawa, Munehide Nakatsugawa, Shiro Suzuki, Hirofumi Shirakawa, Daisuke Nobuoka, Noriko Sakemura, Yutaka Motomura, Yukie Tanaka, Shin Ichi Hayashi, Tetsuya Nakatsura

Research output: Contribution to journalArticle

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Abstract

Glypican-3 (GPC3) is an onco-fetal antigen that is overexpressed in human hepatocellular carcinoma (HCC), and is only expressed in the placenta and embryonic liver among normal tissues. Previously, we identified an HLA-A2-restricted GPC3144-152 (FVGEFFTDV) peptide that can induce GPC3-reactive CTLs without inducing autoimmunity in HLA-A2 transgenic mice. In this study, we carried out a phase I clinical trial of HLA-A2-restricted GPC3144-152 peptide vaccine in 14 patients with advanced HCC. Immunological responses were analyzed by ex vivoγ-interferon enzyme-linked immunospot assay. The frequency of GPC3144-152 peptide-specific CTLs after vaccination (mean, 96; range, 5-441) was significantly larger than that before vaccination (mean, 6.5; range, 0-43) (P144-152 peptide-specific CTL frequency was observed in 12 (86%) of 14 patients after vaccination. Additionally, there was a significant correlation between the maximum value of GPC3144-152 peptide-specific CTLs after vaccination and the dose of the peptide injected (P=0.0166, r=0.665). Moreover, we established several GPC3144-152 peptide-specific CTL clones from PBMCs of patients vaccinated with GPC3144-152 peptide by single cell sorting using Dextramer and CD107a antibody. These CTL clones had high avidity (the recognition efficiency showing 50% cytotoxicity was 10-10 or 10-11M) and could recognize HCC cell lines expressing GPC3 in an HLA-class I-restricted manner. These results suggest that GPC3144-152 peptide vaccine can induce high avidity CTLs capable of killing HCC cells expressing GPC3. This trial was registered with University Hospital Medical Information Network number 000001395.

Original languageEnglish
Pages (from-to)918-925
Number of pages8
JournalCancer Science
Volume102
Issue number5
DOIs
Publication statusPublished - May 2011
Externally publishedYes

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Glypicans
HLA-A2 Antigen
Subunit Vaccines
Clone Cells
Hepatocellular Carcinoma
Antigens
Vaccination
Peptides
Neoplasms
Enzyme-Linked Immunospot Assay
Clinical Trials, Phase I
Information Services
Autoimmunity
Interferons
Placenta
Transgenic Mice
Cell Line
Antibodies
Liver

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

HLA-A2-restricted glypican-3 peptide-specific CTL clones induced by peptide vaccine show high avidity and antigen-specific killing activity against tumor cells. / Yoshikawa, Toshiaki; Nakatsugawa, Munehide; Suzuki, Shiro; Shirakawa, Hirofumi; Nobuoka, Daisuke; Sakemura, Noriko; Motomura, Yutaka; Tanaka, Yukie; Hayashi, Shin Ichi; Nakatsura, Tetsuya.

In: Cancer Science, Vol. 102, No. 5, 05.2011, p. 918-925.

Research output: Contribution to journalArticle

Yoshikawa, T, Nakatsugawa, M, Suzuki, S, Shirakawa, H, Nobuoka, D, Sakemura, N, Motomura, Y, Tanaka, Y, Hayashi, SI & Nakatsura, T 2011, 'HLA-A2-restricted glypican-3 peptide-specific CTL clones induced by peptide vaccine show high avidity and antigen-specific killing activity against tumor cells', Cancer Science, vol. 102, no. 5, pp. 918-925. https://doi.org/10.1111/j.1349-7006.2011.01896.x
Yoshikawa, Toshiaki ; Nakatsugawa, Munehide ; Suzuki, Shiro ; Shirakawa, Hirofumi ; Nobuoka, Daisuke ; Sakemura, Noriko ; Motomura, Yutaka ; Tanaka, Yukie ; Hayashi, Shin Ichi ; Nakatsura, Tetsuya. / HLA-A2-restricted glypican-3 peptide-specific CTL clones induced by peptide vaccine show high avidity and antigen-specific killing activity against tumor cells. In: Cancer Science. 2011 ; Vol. 102, No. 5. pp. 918-925.
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abstract = "Glypican-3 (GPC3) is an onco-fetal antigen that is overexpressed in human hepatocellular carcinoma (HCC), and is only expressed in the placenta and embryonic liver among normal tissues. Previously, we identified an HLA-A2-restricted GPC3144-152 (FVGEFFTDV) peptide that can induce GPC3-reactive CTLs without inducing autoimmunity in HLA-A2 transgenic mice. In this study, we carried out a phase I clinical trial of HLA-A2-restricted GPC3144-152 peptide vaccine in 14 patients with advanced HCC. Immunological responses were analyzed by ex vivoγ-interferon enzyme-linked immunospot assay. The frequency of GPC3144-152 peptide-specific CTLs after vaccination (mean, 96; range, 5-441) was significantly larger than that before vaccination (mean, 6.5; range, 0-43) (P144-152 peptide-specific CTL frequency was observed in 12 (86{\%}) of 14 patients after vaccination. Additionally, there was a significant correlation between the maximum value of GPC3144-152 peptide-specific CTLs after vaccination and the dose of the peptide injected (P=0.0166, r=0.665). Moreover, we established several GPC3144-152 peptide-specific CTL clones from PBMCs of patients vaccinated with GPC3144-152 peptide by single cell sorting using Dextramer and CD107a antibody. These CTL clones had high avidity (the recognition efficiency showing 50{\%} cytotoxicity was 10-10 or 10-11M) and could recognize HCC cell lines expressing GPC3 in an HLA-class I-restricted manner. These results suggest that GPC3144-152 peptide vaccine can induce high avidity CTLs capable of killing HCC cells expressing GPC3. This trial was registered with University Hospital Medical Information Network number 000001395.",
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