Phase I trial of a glypican-3-derived peptide vaccine for advanced hepatocellular carcinoma

Immunologic evidence and potential for improving overall survival

Yu Sawada, Toshiaki Yoshikawa, Daisuke Nobuoka, Hirofumi Shirakawa, Toshimitsu Kuronuma, Yutaka Motomura, Shoichi Mizuno, Hiroshi Ishii, Kohei Nakachi, Masaru Konishi, Toshio Nakagohri, Shinichiro Takahashi, Naoto Gotohda, Tadatoshi Takayama, Kenji Yamao, Katsuhiko Uesaka, Junji Furuse, Taira Kinoshita, Tetsuya Nakatsura

Research output: Contribution to journalArticle

131 Citations (Scopus)

Abstract

Purpose: The carcinoembryonic antigen glypican-3 (GPC3) is an ideal target of anticancer immunotherapy against hepatocellular carcinoma (HCC). In this nonrandomized, open-label, phase I clinical trial, we analyzed the safety and efficacy of GPC3 peptide vaccination in patients with advanced HCC. Experimental Design: Thirty-three patients with advanced HCC underwent GPC3 peptide vaccination (intradermal injections on days 1, 15, and 29 with dose escalation). The primary endpoint was the safety of GPC3 peptide vaccination. The secondary endpoints were immune response, as measured by IFN-g ELISPOT assay, and the clinical outcomes tumor response, time to tumor progression, and overall survival (OS). Results: GPC3 vaccination was well-tolerated. One patient showed a partial response, and 19 patients showed stable disease 2 months after initiation of treatment. Four of the 19 patients with stable disease had tumor necrosis or regression that did not meet the criteria for a partial response. Levels of the tumor markers a-fetoprotein and/or des-g-carboxy prothrombin temporarily decreased in nine patients. The GPC3 peptide vaccine induced a GPC3-specific CTL response in 30 patients. Furthermore, GPC3-specific CTL frequency after vaccination correlated with OS. OS was significantly longer in patients with high GPC3-specific CTL frequencies (N = 15) than in those with low frequencies (N = 18; P = 0.033). Conclusions: GPC3-derived peptide vaccination was well-tolerated, and measurable immune responses and antitumor efficacy were noted. This is the first study to show that peptide-specific CTL frequency can be a predictive marker of OS in patients with HCC receiving peptide vaccination.

Original languageEnglish
Pages (from-to)3686-3696
Number of pages11
JournalClinical Cancer Research
Volume18
Issue number13
DOIs
Publication statusPublished - Jul 1 2012
Externally publishedYes

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Glypicans
Subunit Vaccines
Hepatocellular Carcinoma
Survival
Vaccination
Peptides
Fetal Proteins
Safety
Enzyme-Linked Immunospot Assay
Intradermal Injections
Neoplasms
Clinical Trials, Phase I
Carcinoembryonic Antigen
Prothrombin
Tumor Biomarkers
Immunotherapy
Reaction Time
Research Design
Necrosis

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Phase I trial of a glypican-3-derived peptide vaccine for advanced hepatocellular carcinoma : Immunologic evidence and potential for improving overall survival. / Sawada, Yu; Yoshikawa, Toshiaki; Nobuoka, Daisuke; Shirakawa, Hirofumi; Kuronuma, Toshimitsu; Motomura, Yutaka; Mizuno, Shoichi; Ishii, Hiroshi; Nakachi, Kohei; Konishi, Masaru; Nakagohri, Toshio; Takahashi, Shinichiro; Gotohda, Naoto; Takayama, Tadatoshi; Yamao, Kenji; Uesaka, Katsuhiko; Furuse, Junji; Kinoshita, Taira; Nakatsura, Tetsuya.

In: Clinical Cancer Research, Vol. 18, No. 13, 01.07.2012, p. 3686-3696.

Research output: Contribution to journalArticle

Sawada, Y, Yoshikawa, T, Nobuoka, D, Shirakawa, H, Kuronuma, T, Motomura, Y, Mizuno, S, Ishii, H, Nakachi, K, Konishi, M, Nakagohri, T, Takahashi, S, Gotohda, N, Takayama, T, Yamao, K, Uesaka, K, Furuse, J, Kinoshita, T & Nakatsura, T 2012, 'Phase I trial of a glypican-3-derived peptide vaccine for advanced hepatocellular carcinoma: Immunologic evidence and potential for improving overall survival', Clinical Cancer Research, vol. 18, no. 13, pp. 3686-3696. https://doi.org/10.1158/1078-0432.CCR-11-3044
Sawada, Yu ; Yoshikawa, Toshiaki ; Nobuoka, Daisuke ; Shirakawa, Hirofumi ; Kuronuma, Toshimitsu ; Motomura, Yutaka ; Mizuno, Shoichi ; Ishii, Hiroshi ; Nakachi, Kohei ; Konishi, Masaru ; Nakagohri, Toshio ; Takahashi, Shinichiro ; Gotohda, Naoto ; Takayama, Tadatoshi ; Yamao, Kenji ; Uesaka, Katsuhiko ; Furuse, Junji ; Kinoshita, Taira ; Nakatsura, Tetsuya. / Phase I trial of a glypican-3-derived peptide vaccine for advanced hepatocellular carcinoma : Immunologic evidence and potential for improving overall survival. In: Clinical Cancer Research. 2012 ; Vol. 18, No. 13. pp. 3686-3696.
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AU - Yoshikawa, Toshiaki

AU - Nobuoka, Daisuke

AU - Shirakawa, Hirofumi

AU - Kuronuma, Toshimitsu

AU - Motomura, Yutaka

AU - Mizuno, Shoichi

AU - Ishii, Hiroshi

AU - Nakachi, Kohei

AU - Konishi, Masaru

AU - Nakagohri, Toshio

AU - Takahashi, Shinichiro

AU - Gotohda, Naoto

AU - Takayama, Tadatoshi

AU - Yamao, Kenji

AU - Uesaka, Katsuhiko

AU - Furuse, Junji

AU - Kinoshita, Taira

AU - Nakatsura, Tetsuya

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N2 - Purpose: The carcinoembryonic antigen glypican-3 (GPC3) is an ideal target of anticancer immunotherapy against hepatocellular carcinoma (HCC). In this nonrandomized, open-label, phase I clinical trial, we analyzed the safety and efficacy of GPC3 peptide vaccination in patients with advanced HCC. Experimental Design: Thirty-three patients with advanced HCC underwent GPC3 peptide vaccination (intradermal injections on days 1, 15, and 29 with dose escalation). The primary endpoint was the safety of GPC3 peptide vaccination. The secondary endpoints were immune response, as measured by IFN-g ELISPOT assay, and the clinical outcomes tumor response, time to tumor progression, and overall survival (OS). Results: GPC3 vaccination was well-tolerated. One patient showed a partial response, and 19 patients showed stable disease 2 months after initiation of treatment. Four of the 19 patients with stable disease had tumor necrosis or regression that did not meet the criteria for a partial response. Levels of the tumor markers a-fetoprotein and/or des-g-carboxy prothrombin temporarily decreased in nine patients. The GPC3 peptide vaccine induced a GPC3-specific CTL response in 30 patients. Furthermore, GPC3-specific CTL frequency after vaccination correlated with OS. OS was significantly longer in patients with high GPC3-specific CTL frequencies (N = 15) than in those with low frequencies (N = 18; P = 0.033). Conclusions: GPC3-derived peptide vaccination was well-tolerated, and measurable immune responses and antitumor efficacy were noted. This is the first study to show that peptide-specific CTL frequency can be a predictive marker of OS in patients with HCC receiving peptide vaccination.

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