Predictive biomarkers for the efficacy of peptide vaccine treatment

based on the results of a phase II study on advanced pancreatic cancer

Yoshitaro Shindo, Shoichi Hazama, Nobuaki Suzuki, Haruo Iguchi, Kazuhiro Uesugi, Hiroaki Tanaka, Atsushi Aruga, Takashi Hatori, Hidenobu Ishizaki, Yuzo Umeda, Toshiyoshi Fujiwara, Tetsuya Ikemoto, Mitsuo Shimada, Kazuhiko Yoshimatsu, Hiroko Takenouchi, Hiroto Matsui, Shinsuke Kanekiyo, Michihisa Iida, Yasunobu Koki, Hideki Arima & 8 others Hiroyuki Furukawa, Tomio Ueno, Shigefumi Yoshino, Tomonobu Fujita, Yutaka Kawakami, Yusuke Nakamura, Masaaki Oka, Hiroaki Nagano

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

BACKGROUND: The purpose of the present study was to explore novel biomarkers that can predict the clinical outcome of patients before treatment or during vaccination. These would be useful for the selection of appropriate patients who would be expected to exhibit better treatment outcomes from vaccination, and for facilitating the development of cancer vaccine treatments.

METHODS: From a single-arm, non-randomized, human leukocyte antigen (HLA)-A-status-blind phase II trial of a vaccine treatment using three HLA-A*2402-restricted peptides for advanced pancreatic cancer (PC), we obtained peripheral blood samples from 36 patients of an HLA-A*2402-matched group and 27 patients of an HLA-A*2402-unmatched group.

RESULTS: Multivariate analysis (HR = 2.546; 95% CI = 1.138 to 5.765; p = 0.0231) and log-rank test (p = 0.0036) showed that a high expression level of programmed death-1 (PD-1) on CD4+ T cells was a negative predictive biomarker of overall survival in the HLA-A*2402-matched group . Moreover, a high expression level of PD-1 on CD4+ T cells was a negative predictor for the induction of cytotoxic T lymphocytes (p = 0.0007). After treatment, we found that the upregulation of PD-1 and T cell immunoglobulin mucin-3 (Tim-3) expression on CD4+ and CD8+ T cells was significantly associated with a poor clinical outcome in the HLA-A*2402-matched group (p = 0.0330, 0.0282, 0.0046, and 0.0068, respectively). In contrast, there was no significant difference for these factors in the HLA-A*2402-unmatched group.

CONCLUSIONS: Our results indicate that the upregulation of PD-1 and Tim-3 expression on CD4+ and CD8+ T cells may restrict T cell responses in advanced PC patients; therefore, combination immunotherapy with blockade of PD-1 and Tim-3 to restore T cell responses may be a potential therapeutic approach for advanced PC patients.

TRIAL REGISTRATION: Clinical-Trail-Registration: UMIN000008082 .

Original languageEnglish
Number of pages1
JournalJournal of experimental & clinical cancer research : CR
Volume36
Issue number1
DOIs
Publication statusPublished - Feb 28 2017
Externally publishedYes

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Subunit Vaccines
Pancreatic Neoplasms
HLA Antigens
Biomarkers
T-Lymphocytes
Mucin-3
Immunoglobulins
Research Design
Therapeutics
Vaccination
Up-Regulation
Cancer Vaccines
Cytotoxic T-Lymphocytes
Immunotherapy
Patient Selection
Vaccines
Multivariate Analysis
Peptides
Survival

Keywords

  • Pancreatic cancer
  • PD-1
  • Peptide vaccine
  • Predictive biomarker
  • Tim-3

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Predictive biomarkers for the efficacy of peptide vaccine treatment : based on the results of a phase II study on advanced pancreatic cancer. / Shindo, Yoshitaro; Hazama, Shoichi; Suzuki, Nobuaki; Iguchi, Haruo; Uesugi, Kazuhiro; Tanaka, Hiroaki; Aruga, Atsushi; Hatori, Takashi; Ishizaki, Hidenobu; Umeda, Yuzo; Fujiwara, Toshiyoshi; Ikemoto, Tetsuya; Shimada, Mitsuo; Yoshimatsu, Kazuhiko; Takenouchi, Hiroko; Matsui, Hiroto; Kanekiyo, Shinsuke; Iida, Michihisa; Koki, Yasunobu; Arima, Hideki; Furukawa, Hiroyuki; Ueno, Tomio; Yoshino, Shigefumi; Fujita, Tomonobu; Kawakami, Yutaka; Nakamura, Yusuke; Oka, Masaaki; Nagano, Hiroaki.

In: Journal of experimental & clinical cancer research : CR, Vol. 36, No. 1, 28.02.2017.

Research output: Contribution to journalArticle

Shindo, Y, Hazama, S, Suzuki, N, Iguchi, H, Uesugi, K, Tanaka, H, Aruga, A, Hatori, T, Ishizaki, H, Umeda, Y, Fujiwara, T, Ikemoto, T, Shimada, M, Yoshimatsu, K, Takenouchi, H, Matsui, H, Kanekiyo, S, Iida, M, Koki, Y, Arima, H, Furukawa, H, Ueno, T, Yoshino, S, Fujita, T, Kawakami, Y, Nakamura, Y, Oka, M & Nagano, H 2017, 'Predictive biomarkers for the efficacy of peptide vaccine treatment: based on the results of a phase II study on advanced pancreatic cancer', Journal of experimental & clinical cancer research : CR, vol. 36, no. 1. https://doi.org/10.1186/s13046-017-0509-1
Shindo, Yoshitaro ; Hazama, Shoichi ; Suzuki, Nobuaki ; Iguchi, Haruo ; Uesugi, Kazuhiro ; Tanaka, Hiroaki ; Aruga, Atsushi ; Hatori, Takashi ; Ishizaki, Hidenobu ; Umeda, Yuzo ; Fujiwara, Toshiyoshi ; Ikemoto, Tetsuya ; Shimada, Mitsuo ; Yoshimatsu, Kazuhiko ; Takenouchi, Hiroko ; Matsui, Hiroto ; Kanekiyo, Shinsuke ; Iida, Michihisa ; Koki, Yasunobu ; Arima, Hideki ; Furukawa, Hiroyuki ; Ueno, Tomio ; Yoshino, Shigefumi ; Fujita, Tomonobu ; Kawakami, Yutaka ; Nakamura, Yusuke ; Oka, Masaaki ; Nagano, Hiroaki. / Predictive biomarkers for the efficacy of peptide vaccine treatment : based on the results of a phase II study on advanced pancreatic cancer. In: Journal of experimental & clinical cancer research : CR. 2017 ; Vol. 36, No. 1.
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T1 - Predictive biomarkers for the efficacy of peptide vaccine treatment

T2 - based on the results of a phase II study on advanced pancreatic cancer

AU - Shindo, Yoshitaro

AU - Hazama, Shoichi

AU - Suzuki, Nobuaki

AU - Iguchi, Haruo

AU - Uesugi, Kazuhiro

AU - Tanaka, Hiroaki

AU - Aruga, Atsushi

AU - Hatori, Takashi

AU - Ishizaki, Hidenobu

AU - Umeda, Yuzo

AU - Fujiwara, Toshiyoshi

AU - Ikemoto, Tetsuya

AU - Shimada, Mitsuo

AU - Yoshimatsu, Kazuhiko

AU - Takenouchi, Hiroko

AU - Matsui, Hiroto

AU - Kanekiyo, Shinsuke

AU - Iida, Michihisa

AU - Koki, Yasunobu

AU - Arima, Hideki

AU - Furukawa, Hiroyuki

AU - Ueno, Tomio

AU - Yoshino, Shigefumi

AU - Fujita, Tomonobu

AU - Kawakami, Yutaka

AU - Nakamura, Yusuke

AU - Oka, Masaaki

AU - Nagano, Hiroaki

PY - 2017/2/28

Y1 - 2017/2/28

N2 - BACKGROUND: The purpose of the present study was to explore novel biomarkers that can predict the clinical outcome of patients before treatment or during vaccination. These would be useful for the selection of appropriate patients who would be expected to exhibit better treatment outcomes from vaccination, and for facilitating the development of cancer vaccine treatments.METHODS: From a single-arm, non-randomized, human leukocyte antigen (HLA)-A-status-blind phase II trial of a vaccine treatment using three HLA-A*2402-restricted peptides for advanced pancreatic cancer (PC), we obtained peripheral blood samples from 36 patients of an HLA-A*2402-matched group and 27 patients of an HLA-A*2402-unmatched group.RESULTS: Multivariate analysis (HR = 2.546; 95% CI = 1.138 to 5.765; p = 0.0231) and log-rank test (p = 0.0036) showed that a high expression level of programmed death-1 (PD-1) on CD4+ T cells was a negative predictive biomarker of overall survival in the HLA-A*2402-matched group . Moreover, a high expression level of PD-1 on CD4+ T cells was a negative predictor for the induction of cytotoxic T lymphocytes (p = 0.0007). After treatment, we found that the upregulation of PD-1 and T cell immunoglobulin mucin-3 (Tim-3) expression on CD4+ and CD8+ T cells was significantly associated with a poor clinical outcome in the HLA-A*2402-matched group (p = 0.0330, 0.0282, 0.0046, and 0.0068, respectively). In contrast, there was no significant difference for these factors in the HLA-A*2402-unmatched group.CONCLUSIONS: Our results indicate that the upregulation of PD-1 and Tim-3 expression on CD4+ and CD8+ T cells may restrict T cell responses in advanced PC patients; therefore, combination immunotherapy with blockade of PD-1 and Tim-3 to restore T cell responses may be a potential therapeutic approach for advanced PC patients.TRIAL REGISTRATION: Clinical-Trail-Registration: UMIN000008082 .

AB - BACKGROUND: The purpose of the present study was to explore novel biomarkers that can predict the clinical outcome of patients before treatment or during vaccination. These would be useful for the selection of appropriate patients who would be expected to exhibit better treatment outcomes from vaccination, and for facilitating the development of cancer vaccine treatments.METHODS: From a single-arm, non-randomized, human leukocyte antigen (HLA)-A-status-blind phase II trial of a vaccine treatment using three HLA-A*2402-restricted peptides for advanced pancreatic cancer (PC), we obtained peripheral blood samples from 36 patients of an HLA-A*2402-matched group and 27 patients of an HLA-A*2402-unmatched group.RESULTS: Multivariate analysis (HR = 2.546; 95% CI = 1.138 to 5.765; p = 0.0231) and log-rank test (p = 0.0036) showed that a high expression level of programmed death-1 (PD-1) on CD4+ T cells was a negative predictive biomarker of overall survival in the HLA-A*2402-matched group . Moreover, a high expression level of PD-1 on CD4+ T cells was a negative predictor for the induction of cytotoxic T lymphocytes (p = 0.0007). After treatment, we found that the upregulation of PD-1 and T cell immunoglobulin mucin-3 (Tim-3) expression on CD4+ and CD8+ T cells was significantly associated with a poor clinical outcome in the HLA-A*2402-matched group (p = 0.0330, 0.0282, 0.0046, and 0.0068, respectively). In contrast, there was no significant difference for these factors in the HLA-A*2402-unmatched group.CONCLUSIONS: Our results indicate that the upregulation of PD-1 and Tim-3 expression on CD4+ and CD8+ T cells may restrict T cell responses in advanced PC patients; therefore, combination immunotherapy with blockade of PD-1 and Tim-3 to restore T cell responses may be a potential therapeutic approach for advanced PC patients.TRIAL REGISTRATION: Clinical-Trail-Registration: UMIN000008082 .

KW - Pancreatic cancer

KW - PD-1

KW - Peptide vaccine

KW - Predictive biomarker

KW - Tim-3

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