Predictive biomarkers for the efficacy of peptide vaccine treatment: based on the results of a phase II study on advanced pancreatic cancer.

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 .

• Authors: 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, Hiroyuki Furukawa, Tomio Ueno, Shigefumi Yoshino, Tomonobu Fujita, Yutaka Kawakami, Yusuke Nakamura, Masaaki Oka, Hiroaki Nagano
• Journal: Journal of experimental & clinical cancer research : CR (J Exp Clin Cancer Res) Vol. 36 Issue 1 Pg. 36 (02 28 2017) ISSN: 1756-9966 [Electronic] England
• PMID: 28241889 (Publication Type: Clinical Trial, Phase II, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers, Tumor
• Cancer Vaccines
• HAVCR2 protein, human
• HLA-A*24:02 antigen
• HLA-A24 Antigen
• Hepatitis A Virus Cellular Receptor 2
• PDCD1 protein, human
• Programmed Cell Death 1 Receptor
• Vaccines, Subunit

Topics

• Aged
• Biomarkers, Tumor (blood)
• CD4-Positive T-Lymphocytes (metabolism)
• CD8-Positive T-Lymphocytes (metabolism)
• Cancer Vaccines (administration & dosage, therapeutic use)
• Female
• Gene Expression Regulation, Neoplastic
• HLA-A24 Antigen (chemistry)
• Hepatitis A Virus Cellular Receptor 2 (blood)
• Humans
• Male
• Middle Aged
• Pancreatic Neoplasms (drug therapy, immunology, pathology)
• Programmed Cell Death 1 Receptor (blood)
• Treatment Outcome
• Up-Regulation
• Vaccines, Subunit (administration & dosage, therapeutic use)