Clinical Trials Study
Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Oct 21, 2015; 21(39): 11168-11178
Published online Oct 21, 2015. doi: 10.3748/wjg.v21.i39.11168
Prognostic significance of plasma interleukin-6/-8 in pancreatic cancer patients receiving chemoimmunotherapy
Shintaro Tsukinaga, Mikio Kajihara, Kazuki Takakura, Zensho Ito, Tomoya Kanai, Keisuke Saito, Shinichiro Takami, Hiroko Kobayashi, Yoshihiro Matsumoto, Shunichi Odahara, Kan Uchiyama, Hiroshi Arakawa, Masato Okamoto, Haruo Sugiyama, Kazuki Sumiyama, Toshifumi Ohkusa, Shigeo Koido
Shintaro Tsukinaga, Mikio Kajihara, Kazuki Takakura, Zensho Ito, Tomoya Kanai, Keisuke Saito, Shinichiro Takami, Hiroko Kobayashi, Yoshihiro Matsumoto, Shunichi Odahara, Kan Uchiyama, Toshifumi Ohkusa, Shigeo Koido, Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Kashiwa City, Chiba 277-8567, Japan
Shintaro Tsukinaga, Hiroshi Arakawa, Kazuki Sumiyama, Department of Endoscopy, The Jikei University School of Medicine, Minato City, Tokyo 105-8461, Japan
Masato Okamoto, Department of Advanced Immunotherapeutics, Kitasato University School of Pharmacy, Tokyo 108-8641, Japan
Toshifumi Ohkusa, Shigeo Koido, Institute of Clinical Medicine and Research, The Jikei University School of Medicine, Kashiwa City, Chiba 277-8564, Japan
Haruo Sugiyama, Department of Functional Diagnostic Science, Graduate School of Medicine, Osaka University, Suita City, Osaka 565-0871, Japan
Author contributions: Koido S, Ohkusa T, Sugiyama H, Okamoto M, Sumiyama K designed the research; Tsukinaga S, Kajihara M, Takakura K, Ito Z, Kanai T, Saito K, Takami S, Kobayashi H, Matsumoto Y, Odahara S, Uchiyama K, Arakawa H performed the research, analyzed the data; and Tsukinaga S, Koido S wrote the paper.
Supported by Grants-in-Aid for Scientific Research (C) from the Ministry of Education, Culture, Sports, Science and Technology of Japan.
Institutional review board statement: The study was reviewed and approved by the ethics committee of the Jikei Institutional Review Board, Jikei University School of Medicine (Tokyo, Japan), and the clinical study committee of Jikei University Kashiwa Hospital [No. 14-60 (3209) and No. 21-204 (6082)].
Informed consent statement: All study participants, or their legal guardian, provided informed written consent prior to study enrollment. The procedures were performed in accordance with the Helsinki Declaration.
Conflict-of-interest statement: Okamoto M holds ownership interest in Tella, Inc. Sugiyama H is the inventor of patents PCT/JP02/02794 and PCT/JP04/16336 which are held by the International Institute of Cancer Immunotherapy. No potential conflicts of interest were disclosed by the other authors.
Data sharing statement: No additional data are available.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Shigeo Koido, MD, Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, 163-1 Kashiwa-shita, Kashiwa, Chiba 277-8567, Japan. shigeo_koido@jikei.ac.jp
Telephone: +81-4-7164-1111 Fax: +81-4-7163-3488
Received: July 2, 2015
Peer-review started: July 6, 2015
First decision: July 19, 2015
Revised: August 2, 2015
Accepted: August 30, 2015
Article in press: August 30, 2015
Published online: October 21, 2015
Abstract

AIM: To investigate the association of plasma levels of interleukin (IL)-6 and -8 with Wilms’ tumor 1 (WT1)-specific immune responses and clinical outcomes in patients with pancreatic ductal adenocarcinoma (PDA) treated with dendritic cells (DCs) pulsed with three types of major histocompatibility complex class I and II-restricted WT1 peptides combined with chemotherapy.

METHODS: During the entire treatment period, plasma levels of IL-6 and -8 were analyzed by ELISA. The induction of WT1-specific immune responses was assessed using the WT1 peptide-specific delayed-type hypersensitivity (DTH) test.

RESULTS: Three of 7 patients displayed strong WT1-DTH reactions throughout long-term vaccination with significantly decreased levels of IL-6/-8 after vaccinations compared with the levels prior to treatment. Moreover, overall survival (OS) was significantly longer in PDA patients with low plasma IL-6 levels (< 2 pg/mL) after 5 vaccinations than in patients with high plasma IL-6 levels (≥ 2 pg/mL) (P = 0.025). After disease progression, WT1-DTH reactions decreased severely and were ultimately negative at the terminal stage of cancer. The decreased levels of IL-6/-8 observed throughout long-term vaccination were associated with WT1-specific DTH reactions and long-term OS.

CONCLUSION: Prolonged low levels of plasma IL-6/-8 in PDA patients may be a prognostic marker for the clinical outcomes of chemoimmunotherapy.

Keywords: Chemoimmunotherapy, Dendritic cell, Delayed-type hypersensitivity, Interleukin-6, Interleukin-8, Pancreatic cancer, Wilms’ tumor 1

Core tip: We recently reported a phase 1 clinical study in pancreatic cancer patients using dendritic cells (DCs) pulsed with multiple major histocompatibility complex class I and II-restricted Wilms’ tumor 1 (WT1) epitopes (DC/WT1-I/II) in combination with chemotherapy. Little is known about the prognostic markers for the clinical outcomes of chemoimmunotherapy. We examined the association of plasma levels of interleukin (IL)-6/-8 with WT1-specific immune responses and clinical outcomes in pancreatic cancer patients treated with chemotherapy combined with DC/WT1-I/II. The study demonstrates that prolonged low levels of plasma IL-6/-8 in pancreatic ductal adenocarcinoma patients may be a prognostic marker for the clinical outcomes of chemoimmunotherapy.