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| 1.
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Mukaida, Naofumi ; Nakamoto, Yasunari ; 向田, 直史 ; 中本, 安成
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金沢大学がん進展制御研究所<br />Tumor immunity proceeds through multiple processes, which consist of antigen presentation by antigen
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presenting cells (APCs) to educate effector cells and destruction by the effector cytotoxic cells. However, tumor immunity is frequently repressed at tumor sites. Malignantly transformed cells rarely survive the attack by the immune system, but cells that do survive change their phenotypes to reduce their immunogenicity. The resultant cells evade the attack by the immune system and form clinically discernible tumors. Tumor microenvironments simultaneously contain a wide variety of immune suppressive molecules and cells to dampen tumor immunity. Moreover, the liver microenvironment exhibits immune tolerance to reduce aberrant immune responses to massively-exposed antigens via the portal vein, and immune dysfunction is frequently associated with liver cirrhosis, which is widespread in hepatocellular carcinoma (HCC) patients. Immune therapy aims to reduce tumor burden, but it is also expected to prevent non-cancerous liver lesions from progressing to HCC, because HCC develops or recurs from noncancerous liver lesions with chronic inflammatory states and/or cirrhosis and these lesions cannot be cured and/or eradicated by local and/or systemic therapies. Nevertheless, cancer immune therapy should augment specific tumor immunity by using two distinct measures: enhancing the effector cell functions such as antigen presentation capacity of APCs and tumor cell killing capacity of cytotoxic cells, and reactivating the immune system in immune-suppressive tumor microenvironments. Here, we will summarize the current status and discuss the future perspective on immune therapy for HCC. © The Author(s) 2018.<br />Supported by (in part) Research Programs on the Innovative Development and Application for New Drugs for Hepatitis B (No. 17fk0310116h0001) from the Japan Agency for Medical Research and Development (AMED) and Extramural Collaborative Research Grant of Cancer Research Institute, Kanazawa University.
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| 2.
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中本, 安成 ; Nakamoto, Yasunari
概要:
取得学位 : 博士（医学）, 学位授与番号 : 医博甲第1076号, 学位授与年月日：平成5年3月25日,学位授与年：1993
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| 3.
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Iida, Noriho ; Nakamoto, Yasunari ; Baba, Tomohisa ; Nakagawa, Hidetoshi ; Mizukoshi, Eishiro ; Naito, Makoto ; Mukaida, Naofumi ; Kaneko, Shuichi
概要:
金沢大学医薬保健研究域医学系<br />Several chemokines are used for immunotherapy against cancers because they can attract immune cells
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such as dendritic and cytotoxic T cells to augment immune responses. Radiofrequency ablation (RFA) is used to locally eliminate cancers such as hepatocellular carcinoma (HCC), renal cell carcinoma, and lung cancer. Because HCC often recurs even after an eradicative treatment with RFA, additional immunotherapy is necessary. We treated tumor-bearing mice by administering ECI301, an active variant of CC chemokine ligand 3, after RFA. Mice were injected s.c. with BNL 1ME A.7R.1, a murine hepatoma cell line, in the bilateral flank. After the tumor became palpable, RFA was done on the tumor of one flank with or without ECI301. RFA alone eliminated the treated ipsilateral tumors and retarded the growth of contralateral non-RFA-treated tumors accompanied by massive T-cell infiltration. Injection of ECI301 augmented RFA-induced antitumor effect against non-RFA-treated tumors when administered to wild-type or CCR5-deficient but not CCR1-deficient mice. ECI301 also increased CCR1-expressing CD11c+ cells in peripheral blood and RFA-treated tumors after RFA. Deficiency of CCR1 impairs accumulation of CD11c+, CD4+, and CD8+ cells in RFA-treated tumors. Furthermore, in IFN-ã-enzyme-linked immunospot assay, ECI301 augmented tumor-specific responses after RFA whereas deficiency of CCR1 abolished this augmentation. Thus, we proved that ECI301 further augments RFA-induced antitumor immune responses in a CCR1-dependent manner. ©2010 AACR.
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| 4.
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Honda, Masao ; Sakai, Yoshio ; Yamashita, Taro ; Yamashita, Tatsuya ; Sakai, Akito ; Mizukoshi, Eishiro ; Nakamoto, Yasunari ; Tatsumi, Isamu ; Miyazaki, Yoshitaka ; Tanno, Hiroshi ; Kaneko, Shuichi ; Hokuriku Liver Study Group
概要:
金沢大学医薬保健研究域医学系<br />To develop a non-invasive and sensitive diagnostic test for cancer using peripheral blood, we evalua
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ted gene expression profiling of blood obtained from patients with cancer of the digestive system and normal subjects. The expression profiles of blood-derived total RNA obtained from 39 cancer patients (11 colon cancer, 14 gastric cancer, and 14 pancreatic cancer) was clearly different from those obtained from 15 normal subjects. By comparing the gene expression profiles of cancer patients and normal subjects, 25 cancer-differentiating genes (p<5.0×10-6 and fold differences >3) were identified and an " expression index" deduced from the expression values of these genes differentiated the validation cohort (11 colon cancer, 8 gastric cancer, 18 pancreatic cancer, and 15 normal subjects) into cancer patients and normal subjects with 100% (37/37) and 87% (13/15) accuracy, respectively. Although, the expression profiles were not clearly different between the cancer patients, some characteristic genes were identified according to the stage and species of the cancer. Interestingly, many immune-related genes such as antigen presenting, cell cycle accelerating, and apoptosis- and stress-inducing genes were up-regulated in cancer patients, reflecting the active turnover of immune regulatory cells in cancer patients. These results showed the potential relevance of peripheral blood gene expression profiling for the development of new diagnostic examination tools for cancer patients. © 2010 Elsevier Inc.
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| 5.
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Nakamoto, Yasunari ; Mizukoshi, Eishiro ; Kitahara, Masaaki ; Arihara, Fumitaka ; Sakai, Yoshio ; Kakinoki, Kaheita ; Fujita, Yui ; Marukawa, Yohei ; Arai, Kuniaki ; Yamashita, Tatsuya ; Mukaida, Naofumi ; Matsushima, Kouji ; Matsui, Osamu ; Kaneko, Shuichi
概要:
金沢大学医薬保健研究域医学系<br />Despite curative locoregional treatments for hepatocellular carcinoma (HCC), tumour recurrence rates
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remain high. The current study was designed to assess the safety and bioactivity of infusion of dendritic cells (DCs) stimulated with OK432, a streptococcus-derived anti-cancer immunotherapeutic agent, into tumour tissues following transcatheter hepatic arterial embolization (TAE) treatment in patients with HCC. DCs were derived from peripheral blood monocytes of patients with hepatitis C virus-related cirrhosis and HCC in the presence of interleukin (IL)-4 and granulocyte-macrophage colony-stimulating factor and stimulated with 0.1 KE/ml OK432 for 2 days. Thirteen patients were administered with 5 × 106 of DCs through arterial catheter during the procedures of TAE treatment on day 7. The immunomodulatory effects and clinical responses were evaluated in comparison with a group of 22 historical controls treated with TAE but without DC transfer. OK432 stimulation of immature DCs promoted their maturation towards cells with activated phenotypes, high expression of a homing receptor, fairly well-preserved phagocytic capacity, greatly enhanced cytokine production and effective tumoricidal activity. Administration of OK432-stimulated DCs to patients was found to be feasible and safe. Kaplan-Meier analysis revealed prolonged recurrence-free survival of patients treated in this manner compared with the historical controls (P = 0.046, log-rank test). The bioactivity of the transferred DCs was reflected in higher serum concentrations of the cytokines IL-9, IL-15 and tumour necrosis factor-α and the chemokines CCL4 and CCL11. Collectively, this study suggests that a DC-based, active immunotherapeutic strategy in combination with locoregional treatments exerts beneficial anti-tumour effects against liver cancer. © 2010 The Authors. Clinical and Experimental Immunology © 2010 British Society for Immunology.
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| 6.
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Kakinoki, Kaheita ; Nakamoto, Yasunari ; Kagaya, Takashi ; Tsuchiyama, Tomoya ; Sakai, Yoshio ; Nakahama, Tohru ; Mukaida, Naofumi ; Kaneko, Shuichi
概要:
金沢大学医薬保健研究域医学系<br />The prognosis of patients with hepatocellular carcinoma (HCC) remains poor, largely as a result of i
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ntrahepatic metastasis. Using a mouse model of intrahepatic metastasis, we investigated whether chemokine ligand 2/monocyte chemoattractant protein-1 (CCL2/MCP-1) could potentiate the antitumor effects of the herpes simplex virus thymidine kinase/ganciclovir (HSV-tk/GCV) system.Methods: Mouse hepatoma cells infected with recombinant adenovirus vectors expressing HSV-tk, CCL2/MCP-1 and LacZ at multiplicities of infection of Ad-tk/Ad-MCP1 = 3/0.03 (T/MLow), 3/3 (T/MHigh) and Ad-tk/Ad-LacZ = 3/3 (T/L) were injected into BALB/c mice.Results: Intrahepatic tumor growth was significantly lower in T/MLow mice. By contrast, no tumor suppression was observed in T/MHigh mice. The tumor-specific cytolytic activities of splenocytes from T/MLow and T/MHigh mice were comparable. Immunohistochemical analysis of liver tissues showed similar infiltration by Mac-1+ and T cells in these animals, whereas the proportions of classical activated (M1) monocytes/macrophages were significantly higher in T/MLow mice. In addition, interleukin-12 production was elevated in these tissues. Vascular endothelial growth factor-A expression and CD31+ microvessels were increased in T/MHigh mice.Conclusions: Collectively, these results demonstrate that an adequate amount of CCL2/MCP-1, together with the HSV-tk/GCV system, may induce T helper 1-polarized antitumor effects without inducing tumor angiogenesis in the microenvironment of intrahepatic HCC progression. © 2010 John Wiley & Sons, Ltd.
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| 7.
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Yamashita, Tatsuya ; Arai, Kuniaki ; Sunagozaka, Hajime ; Ueda, Teruyuki ; Terashima, Takeshi ; Yamashita, Taro ; Mizukoshi, Eishiro ; Sakai, Akito ; Nakamoto, Yasunari ; Honda, Masao ; Kaneko, Shuichi
概要:
Objective: This randomized phase II trial compared the response rates to treatment with interferon (IFN) combined with h
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epatic arterial infusion of fluorouracil (FU) plus cisplatin (CDDP) or FU alone in patients with advanced hepatocellular carcinoma (HCC). Methods: A total of 114 patients with measurable advanced HCC were enrolled and randomized into 2 groups. FU (300 mg/m2, days 1–5, days 8–12) with or without CDDP (20 mg/m2, days 1 and 8) was administered via the hepatic artery. IFNα-2b was administered 3 times per week for 4 weeks. Results: The response rates were 45.6% for the IFN/FU + CDDP group and 24.6% for the IFN/FU group. The response rate was significantly higher in the IFN/FU + CDDP group (p = 0.030). The median overall survival period was 17.6 months in the IFN/FU + CDDP group versus 10.5 months in the IFN/FU group (p = 0.522). The median progression-free survival period was 6.5 months in the IFN/FU + CDDP group versus 3.3 months in the IFN/FU group (p = 0.0048). Hematological toxicity was common, but no toxicity-related deaths were observed. Conclusion: These results show the clinical efficacy of adding CDDP to the hepatic arterial infusion of FU in combined chemotherapy regimens with IFN.
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| 8.
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Nakagawa, Hidetoshi ; Mizukoshi, Eishiro ; Iida, Noriho ; Terashima, Takeshi ; Kitahara, Masaaki ; Marukawa, Yohei ; Kitamura, Kazuya ; Nakamoto, Yasunari ; Hiroishi, Kazumasa ; Imawari, Michio ; Kaneko, Shuichi
概要:
Radiofrequency ablation therapy (RFA) is a radical treatment for liver cancers and induces tumor antigen-specific immune
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responses. In the present study, we examined the antitumor effects of focal OK-432-stimulated dendritic cell (DC) transfer combined with RFA and analyzed the functional mechanisms involved using a murine model. C57BL/6 mice were injected subcutaneously with colon cancer cells (MC38) in their bilateral flanks. After the establishment of tumors, the subcutaneous tumor on one flank was treated using RFA, and then OK-432-stimulated DCs were injected locally. The antitumor effect of the treatment was evaluated by measuring the size of the tumor on the opposite flank, and the immunological responses were assessed using tumor-infiltrating lymphocytes, splenocytes and draining lymph nodes. Tumor growth was strongly inhibited in mice that exhibited efficient DC migration after RFA and OK-432-stimulated DC transfer, as compared to mice treated with RFA alone or treatment involving immature DC transfer. We also demonstrated that the antitumor effect of this treatment depended on both CD8-positive and CD4-positive cells. On the basis of our findings, we believe that combination therapy for metastatic liver cancer consisting of OK-432-stimulated DCs in combination with RFA can proceed to clinical trials, and it is anticipated to be markedly superior to RFA single therapy. © 2013 Springer-Verlag Berlin Heidelberg.
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| 9.
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Kaneko, Shuichi ; Furuse, Junji ; Kudo, Masatoshi ; Ikeda, Kenji ; Honda, Masao ; Nakamoto, Yasunari ; Onchi, Morikazu ; Shiota, Goshi ; Yokosuka, Osamu ; Sakaida, Isao ; Takehara, Tetsuo ; Ueno, Yoshiyuki ; Hiroishi, Kazumasa ; Nishiguchi, Shuhei ; Moriwaki, Hisataka ; Yamamoto, Kazuhide ; Sata, Michio ; Obi, Shuntaro ; Miyayama, Shiro ; Imai, Yukinori
概要:
The "Guideline on the Use of New Anticancer Drugs for the Treatment of Hepatocellular Carcinoma" was prepared by the Stu
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dy Group on New Liver Cancer Therapies established by the "Research Project on Emergency Measures to Overcome Hepatitis" under the auspices of the Health and Labour Sciences Research Grant. The Guideline brings together data collected by the Study Group on the use and incidence of adverse events in 264 patients with advanced hepatocellular carcinoma (HCC) treated using sorafenib and in 535 patients with advanced HCC treated using miriplatin at 16 participating institutions up until 22 December 2010, as well as referring to the published studies, academic presentations, and reports from the private sector. The aim of this Guideline is to facilitate understanding and current thinking regarding the proper usage of new anticancer drugs towards actual use in therapy. In terms of the format, the Guideline presents "clinical questions" on issues pertaining to medical care, makes "recommendations" on diagnosis and treatment in response to each of these clinical questions, and provides a rationale for these recommendations in the form of "scientific statements". © 2012 The Japan Society of Hepatology.
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| 10.
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Marukawa, Yohei ; Nakamoto, Yasunari ; Kakinoki, Kaheita ; Tsuchiyama, Tomoya ; Iida, Noriho ; Kagaya, Takashi ; Sakai, Yoshio ; Naito, Makoto ; Mukaida, Naofumi ; Kaneko, Shuichi
概要:
Suicide gene therapy using the herpes simplex virus thymidine kinase/ganciclovir (HSV-tk/GCV) system combined with monoc
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yte chemoattractant protein-1 (MCP-1) provides significant antitumor efficacy. The current study was designed to evaluate the antitumor immunity of a newly developed membrane-bound form of MCP-1 (mMCP-1) in an immunocompetent mouse model of hepatocellular carcinoma (HCC). A recombinant adenovirus vector (rAd) harboring the human MCP-1 gene and the membrane-spanning domain of the CX3CL1 gene was used. Large amounts of MCP-1 protein were expressed and accumulated on the tumor cell surface. The growth of subcutaneous tumors was markedly suppressed when tumors were treated with mMCP-1, as compared with soluble MCP-1, in combination with the HSV-tk/GCV system (P<0.01). The numbers of Mac-1-, CD4-and CD8a-positive cells were significantly higher in tumor tissues (P<0.05), and tumor necrosis factor (TNF) mRNA expression levels with mMCP-1 were almost five-fold higher than those with soluble MCP-1. These results indicate that the delivery of the mMCP-1 gene greatly enhanced antitumor effects following the apoptotic stimuli by promoting the recruitment and activation of macrophages and T lymphocytes, suggesting a novel strategy of immune-based gene therapy in the treatment of patients with HCC. © 2012 Macmillan Publishers Limited All rights reserved.
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