title: Predictive biomarkers for the efficacy of peptide vaccine treatment: based on the results of a phase II study on advanced pancreatic cancer.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  Clinical-Trail-Registration: UMIN000008082 .
authors.affiliation: Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi, 755-8505, Japan.
authors.forename: Yoshitaro
authors.initials: Y
authors.lastname: Shindo
authors.affiliation: Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi, 755-8505, Japan.|Department of Translational Research and Developmental Therapeutics against Cancer, Yamaguchi University School of Medicine, Ube, Japan.
authors.forename: Shoichi
authors.initials: S
authors.lastname: Hazama
authors.affiliation: Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi, 755-8505, Japan.
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Suzuki
authors.affiliation: Clinical Research Center, Shikoku Cancer Center, NHO., Matsuyama, Japan.
authors.forename: Haruo
authors.initials: H
authors.lastname: Iguchi
authors.affiliation: Clinical Research Center, Shikoku Cancer Center, NHO., Matsuyama, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Uesugi
authors.affiliation: Department of Surgical Oncology, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Tanaka
authors.affiliation: Institute of Gastroenterology, Tokyo Women's Medical University, Tokyo, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Aruga
authors.affiliation: Institute of Gastroenterology, Tokyo Women's Medical University, Tokyo, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Hatori
authors.affiliation: Department of Surgical Oncology and Regulation of Organ Function, Miyazaki University School of Medicine, Miyazaki, Japan.
authors.forename: Hidenobu
authors.initials: H
authors.lastname: Ishizaki
authors.affiliation: Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Okayama, Japan.
authors.forename: Yuzo
authors.initials: Y
authors.lastname: Umeda
authors.affiliation: Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Okayama, Japan.
authors.forename: Toshiyoshi
authors.initials: T
authors.lastname: Fujiwara
authors.affiliation: Department of Digestive and Transplant Surgery, Tokushima University Graduate School of Medicine, Tokushima, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Ikemoto
authors.affiliation: Department of Digestive and Transplant Surgery, Tokushima University Graduate School of Medicine, Tokushima, Japan.
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Shimada
authors.affiliation: Department of Surgery, Tokyo Women's Medical University Medical Center East, Tokyo, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Yoshimatsu
authors.affiliation: Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi, 755-8505, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Takenouchi
authors.affiliation: Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi, 755-8505, Japan.
authors.forename: Hiroto
authors.initials: H
authors.lastname: Matsui
authors.affiliation: Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi, 755-8505, Japan.
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Kanekiyo
authors.affiliation: Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi, 755-8505, Japan.
authors.forename: Michihisa
authors.initials: M
authors.lastname: Iida
authors.affiliation: Department of Pharmacy, Yamaguchi University Hospital, Ube, Japan.
authors.forename: Yasunobu
authors.initials: Y
authors.lastname: Koki
authors.affiliation: Department of Pharmacy, Yamaguchi University Hospital, Ube, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Arima
authors.affiliation: Department of Pharmacy, Yamaguchi University Hospital, Ube, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Furukawa
authors.affiliation: Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi, 755-8505, Japan.
authors.forename: Tomio
authors.initials: T
authors.lastname: Ueno
authors.affiliation: Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi, 755-8505, Japan.
authors.forename: Shigefumi
authors.initials: S
authors.lastname: Yoshino
authors.affiliation: Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Tomonobu
authors.initials: T
authors.lastname: Fujita
authors.affiliation: Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Kawakami
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois, USA.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nakamura
authors.affiliation: Yamaguchi University, Yamaguchi, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Oka
authors.affiliation: Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi, 755-8505, Japan. hnagano@yamaguchi-u.ac.jp.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Nagano
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000097:blood*; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D019496:Cancer Vaccines / Q000008:administration & dosage* / Q000627:therapeutic use; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D059871:HLA-A24 Antigen / Q000737:chemistry; D000072597:Hepatitis A Virus Cellular Receptor 2 / Q000097:blood; D006801:Humans; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D061026:Programmed Cell Death 1 Receptor / Q000097:blood; D016896:Treatment Outcome; D015854:Up-Regulation; D022223:Vaccines, Subunit / Q000008:administration & dosage* / Q000627:therapeutic use
chemical_list: D014408:Biomarkers, Tumor; D019496:Cancer Vaccines; C448908:HAVCR2 protein, human; C438506:HLA-A*24:02 antigen; D059871:HLA-A24 Antigen; D000072597:Hepatitis A Virus Cellular Receptor 2; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D022223:Vaccines, Subunit
keywords: PD-1; Pancreatic cancer; Peptide vaccine; Predictive biomarker; Tim-3