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| 1.
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Mizukoshi, Eishiro ; Fushimi, Kazumi ; Arai, Kuniaki ; Yamashita, Tatsuya ; Honda, Masao ; Kaneko, Shuichi
概要:
Background & Aims: Chondroitin-glucuronate C5-epimerase is an enzyme that converts D-glucuronic acid to L-iduronic acid
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residues in dermatan sulphate biosynthesis. It is also identified to be a tumour-associated antigen recognized by cytotoxic T cells (CTLs) and its enhanced expression in many cancers has been reported. In the present study, we investigated the usefulness of this molecule as an immunotherapeutic target in hepatocellular carcinoma (HCC). Methods: The expression of chondroitin-glucuronate C5-epimerase in hepatoma cell lines and HCC tissues was confirmed by immunofluorescence and immunohistochemical analysis. CTL responses were investigated by several immunological techniques using peripheral blood mononuclear cells (PBMCs) or tumour-infiltrating lymphocytes. To determine the safety of immunotherapy using chondroitin-glucuronate C5-epimerase-derived peptide, 12 patients with HCC were administered s.c. vaccinations of the peptides and analysed. Results: Chondroitin-glucuronate C5-epimerase was expressed in HCC cell lines and human tissues including alpha-foetoprotein (AFP)-negative individuals. Chondroitin-glucuronate C5-epimerase-specific CTLs could be generated by stimulating PBMCs of HCC patients with peptides and they showed cytotoxicity against HCC cells expressing the protein. The frequency of CTL precursors investigated by enzyme-linked immunospot (ELISPOT) assay was 0-34 cells/3 × 10 5 PBMCs and the infiltration of interferon-gamma-producing CTLs into the tumour site was confirmed. In the vaccination study, no severe adverse events were observed and the peptide-specific CTLs were induced in 4 of 12 patients tested. Conclusions: Chondroitin-glucuronate C5-epimerase is a potential candidate for tumour antigen with immunogenicity and the peptides derived from this antigen could be useful in HCC immunotherapy. © 2012 John Wiley & Sons A/S.
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| 2.
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Kitahara, Masaaki ; Mizukoshi, Eishiro ; Nakamoto, Yasunari ; Mukaida, Naofumi ; Matsushima, Kouji ; Kaneko, Shuichi
概要:
Background & aims Immunotherapy using dendritic cells (DCs) is a promising cancer therapy. The success of this therapy d
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epends on the function of induced DCs. However, there has been no consensus on optimal conditions for DC preparation in vitro for immunotherapy of hepatocellular carcinoma (HCC) patients. To address relevant issues, we evaluated the procedures to induce DCs that efficiently function in hepatitis C virus (HCV)-related HCC. Methods We studied immunological data from 14 HCC patients. The DC preparation and the surface markers were assessed by flow cytometric analysis. Four different additional activation stimuli (Method I, medium alone; Method II, with OK-432; Method III, with IL-1β + IL-6 + TNF-α; Method IV, with IL-1β + IL-6 + TNF-α + PGE2) were tested and the functions of DCs were confirmed by examination of the ability of phagocytosis, cytokine production and allogeneic mixed lymphocyte reaction (MLR). Results The numbers of DCs induced and their cytokine production ability were not different between healthy controls and HCC patients. T-cell stimulatory activity of DCs in MLR was significantly lower in HCC patients than in healthy controls. The maturation of DCs with OK-432 boosted production of cytokines and chemokines, such as IL-2, IL-12p70, IFN-γ, TNF-α, IL-13 and MIP1α, and restored T-cell stimulatory activity of DCs in MLR. Conclusions The clinically approved compound OK-432 is a candidate for highly immunocompetent DC preparation and may be considered as a key drug for immunotherapy of HCV-related HCC patients. © 2014 Published by Elsevier B.V.
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| 3.
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Mizukoshi, Eishiro ; Yamashita, Tatsuya ; Arai, Kuniaki ; Terashima, Takeshi ; Kitahara, Masaaki ; Nakagawa, Hidetoshi ; Iida, Noriho ; Fushimi, Kazumi ; Kaneko, Shuichi
概要:
Hepatic arterial infusion chemotherapy (HAIC) has been employed as an alternative therapy to sorafenib for the patients
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with advanced hepatocellular carcinoma (HCC). In this study, we performed a comparative analysis of various immune cell responses including tumor-associated antigen (TAA)-specific T cells, regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) in advanced HCC patients treated with HAIC. Thirty-six HCC patients were examined in the study. Interferon gamma enzyme-linked immunospot assays were performed to examine the frequency of TAA-specific T cells. The frequencies of Tregs and MDSCs were examined by multicolor fluorescence-activated cell sorting analysis. The treatment with HAIC using interferon (IFN)/5-fluorouracil (FU) or IFN/FU + cisplatin modulated the frequencies of various immune cells. In 22.2 % of patients, the frequency of TAA-specific T cells increased after HAIC. Although the frequency of Tregs decreased after HAIC, it was not associated with the prognosis of patients. An analysis of prognostic factors for overall survival identified diameter of the tumor (<3.0 cm), absence of major portal vein invasion, absence of distant metastasis, Union Internationale Contre Le Cancer tumor lymph node metastasis stage (I or II), neutrophil lymphocytic ratio (<2.1) and the frequency of MDSCs (<30.5 %) as factors that prolonged overall survival time after HAIC. Even in the group adjusted with progressive levels of tumors, patients with a low frequency of MDSCs had a significantly longer overall survival time. In conclusion, the frequency of MDSCs before the treatment is a prognostic factor in HAIC against HCC. © 2016 Springer-Verlag Berlin Heidelberg
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Mizukoshi, Eishiro ; Nakagawa, Hidetoshi ; Kitahara, Masaaki ; Yamashita, Tatsuya ; Arai, Kuniaki ; Sunagozaka, Hajime ; Iida, Noriho ; Fushimi, Kazumi ; Kaneko, Shuichi
概要:
Multidrug resistance-associated protein 3 (MRP3) is a carrier-type transport protein belonging to the ABC transporters.
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In this study, we investigated the safety and immunogenicity of a MRP3-derived peptide (MRP3765) as a vaccine and characterized the MRP3-specific T cell responses induced. Twelve hepatocellular carcinoma (HCC) patients treated with hepatic arterial infusion chemotherapy (HAIC) were enrolled. The MRP3-derived peptide was emulsified in incomplete Freund's adjuvant and administered via subcutaneous immunization three times weekly. No serious adverse drug reactions to the peptide vaccine were observed, and the vaccination was well tolerated. The vaccination induced MRP3-specific immunity in 72.7% of the patients. In a phenotypic analysis, the largest post-vaccinated increase in MRP3-specific T cells was due to an increase in cells with the effector memory phenotype. Among the 12 patients, one patient showed a partial response, nine showed a stable disease, and two showed a progressive disease. The median overall survival time was 14.0 months. In conclusion, the safety, effects of immune boosting, and possible prolongation of overall survival by the MRP3-derived peptide demonstrate the potential of the peptide to provide clinical benefit in HCC patients. © 2015.
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| 5.
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Mizukoshi, Eishiro ; Kaneko, Shuichi
概要:
Hepatocellular carcinoma (HCC) is the sixth most common type of cancer globally. Although many different kinds of treatm
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ent are performed for HCC according to the practical guidelines, the prognosis of patients is not still satisfactory because the effects of treatments are limited for advanced tumors and the recurrence rate of HCC, even in early stages, is very high. Therefore, immunotherapy is highly anticipated as a new treatment method for HCC. For the development of a new HCC therapy, we attempted to establish immunotherapy using dendritic cells (DCs) and peptide vaccine. In several clinical trials that we performed, we confirmed that the immunotherapy was safe and well-tolerated by HCC patients. We observed that DC therapy prolonged the recurrence-free survival of patients compared with that of patients without DC infusion, as well as observing the radiological anti-tumor effect in HCC patients with peptide vaccine. In this chapter, we summarize the results of previous studies using DC and peptide vaccine, including our own data, and describe the prospects of immunotherapy for HCC. © 2015, Springer Japan. All rights reserved.<br />[Book Chapter]
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| 6.
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Nakamoto, Yasunari ; Kaneko, Shuichi ; Fan, Hong ; Momoi, Takashi ; Tsutsui, Hiroko ; Nakanishi, Kenji ; Kobayashi, Kenichi ; Suda, Takashi
概要:
金沢大学がん研究所がん病態制御<br />A persistent immune response to hepatitis viruses is a well-recognized risk factor for hepatocellul
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ar carcinoma. However, the molecular and cellular basis for the procarcinogenic potential of the immune response is not well defined. Here, using a unique animal model of chronic hepatitis that induces hepatocellular carcinogenesis, we demonstrate that neutralization of the activity of Fas ligand prevented hepatocyte apoptosis, proliferation, liver inflammation, and the eventual development of hepatocellular carcinoma. The results indicate that Fas ligand is involved not only in direct hepatocyte killing but also in the process of inflammation and hepatocellular carcinogenesis in chronic hepatitis. This is the first demonstration that amelioration of chronic inflammation by some treatment actually caused reduction of cancer development.
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| 7.
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Nakamoto, Yasunari ; Kaneko, Shuichi ; Fan, Hong ; Momoi, Takashi ; Tsutsui, Hiroko ; Nakanishi, Kenji ; Kobayashi, Kenichi ; Suda, Takashi
概要:
A persistent immune response to hepatitis viruses is a well-recognized risk factor for hepatocellular carcinoma. However, the molecular and cellular basis for the procarcinogenic potential of the immune response is not well defined.
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Here, using a unique animal model of chronic hepatitis that induces hepatocellular carcinogenesis, we demonstrate that neutralization of the activity of Fas ligand prevented hepatocyte apoptosis, proliferation, liver inflammation, and the eventual development of hepatocellular carcinoma. The results indicate that Fas ligand is involved not only in direct hepatocyte killing but also in the process of inflammation and hepatocellular carcinogenesis in chronic hepatitis. This is the first demonstration that amelioration of chronic inflammation by some treatment actually caused reduction of cancer development.
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