Oncotarget

Clinical Research Papers:

Comprehensive immunotherapy combined with intratumoral injection of zoledronate-pulsed dendritic cells, intravenous adoptive activated T lymphocyte and gemcitabine in unresectable locally advanced pancreatic carcinoma: a phase I/II trial

Yoshiki Hirooka _, Hiroki Kawashima, Eizaburo Ohno, Takuya Ishikawa, Takashi Kamigaki, Shigenori Goto, Masashi Takahara and Hidemi Goto

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Oncotarget. 2018; 9:2838-2847. https://doi.org/10.18632/oncotarget.22974

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Abstract

Yoshiki Hirooka1, Hiroki Kawashima2, Eizaburo Ohno2, Takuya Ishikawa2, Takashi Kamigaki3,4, Shigenori Goto3, Masashi Takahara5 and Hidemi Goto2

1Department of Endoscopy, Nagoya University Hospital, Nagoya, Japan

2Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan

3Seta Clinic, Tokyo, Japan

4Department of Next Generation Cell and Immune Therapy, Juntendo University School of Medicine, Tokyo, Japan

5Medinet Medical Institute, MEDINET Co. Ltd., Yokohama, Japan

Correspondence to:

Yoshiki Hirooka, email: hirooka@med.nagoya-u.ac.jp

Keywords: immunotherapy; zoledronate-pulsed DCs; gemcitabine; advanced pancreatic carcinoma; EUS-guided FNA

Received: October 19, 2017     Accepted: November 15, 2017     Published: December 05, 2017

ABSTRACT

Dendritic cell (DC)-based vaccines prepared using various antigen loading methods have been studied for cancer immunotherapy. The in vivo provocation of immunity by the direct injection of DCs without using tumor-specific antigens into tumors after apoptosis-inducing chemotherapy is more applicable. We previously reported that zoledronate-pulsed DCs (Zol-DCs) may induce tumor-antigen-specific CD8+ T cells by activating Vγ9γδT cells. In this report, we studied the feasibility, safety, and efficacy of a comprehensive immunotherapy involving the combined intratumoral injection of Zol-DC, gemcitabine (GEM) and αβT cells in locally advanced pancreatic carcinoma. Seven of 15 patients showed a stable disease (SD) and most of the patients showed long-term clinical responses. The FACT-BRM score was significantly higher in the patients with SD. Additionally the CD8+/Treg ratio significantly increased in SD patients after treatment. The median over-all survival and progression-free-survival of 15 patients were 12.0 months and 5.5 months, respectively. Patients with a pretreatment neutrophil/lymphocyte ratio (NLR) lower than 5.0 showed significantly longer survival. Even in an analysis limited to the patients with an NLR lower than 5.0, the patients whose CD8+/Treg ratio increased more than twofold tended to survive longer. In conclusion, the comprehensive immunotherapy using Zol-DCs, systemic αβT cells, and GEM may synergistically show a therapeutic effect on locally advanced pancreatic carcinoma. By using appropriate and precise biomarkers, such as NLR and CD8+/Treg ratio, the present comprehensive immunotherapy could be more beneficial for patients with pancreatic carcinoma.


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