TY - JOUR
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
N1 - Funding Information:
VENUS-PC study was supported by Ministry of Health Labor, and Welfare of Japan Grant Number H23-cancer-010. The present study was performed as a research program of the Project for Development of Innovative Research on Cancer Therapeutics (P-Direct; 11039020), The Japan Agency for Medical Research and Development (AMED; 15cm0106085h0005), and this study was supported in part by a grant for Leading Advanced Projects for Medical Innovation (LEAP; 16am0001006h0003) from the Japan Agency for Medical Research and Development.
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 - PD-1
KW - Pancreatic cancer
KW - Peptide vaccine
KW - Predictive biomarker
KW - Tim-3
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U2 - 10.1186/s13046-017-0509-1
DO - 10.1186/s13046-017-0509-1
M3 - Article
C2 - 28241889
AN - SCOPUS:85021058742
SN - 0392-9078
VL - 36
SP - 36
JO - Journal of Experimental and Clinical Cancer Research
JF - Journal of Experimental and Clinical Cancer Research
IS - 1
ER -
