新規ケモカイン製剤の免疫賦活効果による肝癌の再発抑制効果をめざした免疫療法の開発

2013 Fiscal Year Annual Research Report

• Project/Area Number: 23790781
• Research Institution: Kanazawa University
• Principal Investigator: 荒井 邦明 金沢大学, 大学病院, 助教 (50436838)
• Keywords: 抗腫瘍免疫

Research Abstract

抗腫瘍免疫を向上させる目的で、C型慢性肝疾患患者由来DCの細胞免疫学的特徴を解明し、種々の刺激誘導法の有用性について検討してきた。肝癌患者由来の未刺激DCでは、非感染者と比較し、生細胞率は低下していたが、DCサブセットにおけるCD11c陽性のミエロイドDCの割合、成熟度を示すCD83およびCD86の発現、遊走能に関与するCCR7の発現は増加（p<0.05）、FITC標識されたデキストランを用いた貪食能も高い傾向にあった。肝癌患者由来DCのOK-432添加群では、他群と比較し、CCR7の発現、Th1タイプのサイトカイン産生（IL-12、IFNγ、TNFα、RANTES、IL-1β、VEGF）、リンパ球刺激能が増加していた（p<0.01）。OK-432添加刺激は抗原提示能、免疫賦活作用を著明に向上させたことから，C型関連肝癌患者に適する樹状細胞調整法が示され新たな免疫治療の開発に寄与する可能性があり，この刺激誘導培養法を用いた樹状細胞をラジオ波焼灼療法施行時に経皮的にがん組織へ注入する安全性臨床試験を開始した．16例のRFAを施行したC型関連肝癌患者に対して，この誘導培養法を用いた樹状細胞を経皮的にがん組織へ注入する安全性臨床試験を行った．有害事象としてgrade2以下の発熱を75%に認めたがRFA自体に伴う副作用であり，重篤な有害事象は認めなかった．以前に当院でRFAを施行した初発肝細胞癌症例と比較し，OK-432添加刺激を加えたDC併用RFA初発肝細胞癌治療症例は，有意に無再発生存期間が延長(p=0.047)した．またOK-432添加刺激を加えずに誘導したDC併用治療群14例と比較したところ，OK-432添加刺激を加えたDC併用治療群は有意に無再発生存期間が延長(p=0.019)することが明らかになった．

Research Products

• [Journal Article] Increase in CD14+HLA-DR -/low myeloid-derived suppressor cells in hepatocellular carcinoma patients and its impact on prognosis (2013)
  • Author(s): Arihara F, Mizukoshi E, Kitahara M, Takata Y, Arai K, Yamashita T, Nakamoto Y, Kaneko S.
  • Journal Title: Cancer Immunol Immunother. Volume: 62 Pages: 1421-30
  • DOI: 10.1007/s00262-013-1447-1
  • Peer Reviewed
• [Journal Article] Association of interleukin-28B genotype and hepatocellular carcinoma recurrence in patients with chronic hepatitis C. (2013)
  • Author(s): Hodo Y, Honda M, Tanaka A, Nomura Y, Arai K, Yamashita T, Sakai Y, Yamashita T, Mizukoshi E, Sakai A, Sasaki M, Nakanuma Y, Moriyama M, Kaneko S.
  • Journal Title: Clin Cancer Res. Volume: 19 Pages: 1827-37
  • DOI: 10.1158/1078-0432.CCR-12-1641
  • Peer Reviewed
• [Journal Article] Peretinoin, an acyclic retinoid, improves the hepatic gene signature of chronic hepatitis C following curative therapy of hepatocellular carcinoma. (2013)
  • Author(s): Honda M, Yamashita T, Yamashita T, Arai K, Sakai Y, Sakai A, Nakamura M, Mizukoshi E, Kaneko S.
  • Journal Title: BMC Cancer. Volume: 15 Pages: 191
  • DOI: 10.1186/1471-2407-13-191
• [Journal Article] Enhancement of tumor-associated antigen-specific T cell responses by radiofrequency ablation of hepatocellular carcinoma. (2013)
  • Author(s): Mizukoshi E, Yamashita T, Arai K, Sunagozaka H, Ueda T, Arihara F, Kagaya T, Yamashita T, Fushimi K, Kaneko S.
  • Journal Title: Hepatology. Volume: 57 Pages: 1448-57
  • DOI: 10.1002/hep.26153
  • Peer Reviewed
• [Presentation] Phase I Trial of Alpha-Fetoprotein-Derived Peptides in the Treatment of Hepatocellular Carcinoma. (2013)
  • Author(s): Eishiro Mizukoshi, Tatsuya Yamashita, Kuniaki Arai, Hajime Sunagozaka, Kazumi Fushimi, Hidetoshi Nakagawa, Kazutoshi Yamada, Kiichiro Kaji, Masaaki Kitahara, Shuichi Kaneko
  • Organizer: AASLD2013
  • Place of Presentation: Washington DC, USA
  • Year and Date: 20131105-20131105
• [Presentation] Serum Dickkopf-1 as a biomarker for the diagnosis of hepatocellular carcinoma with stem cell features. (2013)
  • Author(s): Hajime Sunagozaka, Toro Yamashita, Naoki Oishi, Takehiro Hayashi, Hajime Takatori, Tetsuro Shimakami, Kazuya Kitamura, Kuniaki Arai, Takashi Kagaya, Yoshio Sakai, Tatsuya Yamashita, Eishiro Mizukoshi, Masao Hondo, Shuichi Kaneko
  • Organizer: AASLD2013
  • Place of Presentation: Washington DC, USA
  • Year and Date: 20131105-20131105
• [Presentation] The impact of post-progression survival on overall survival of patients with advanced hepatocellular carcinoma treated by sorafenib therapy. (2013)
  • Author(s): Takeshi Terashima, tatsuya Yamashita, Noboru Takata, Hidetoshi Nakagawa, Kuniaki Arai, Takashi Kagaya, Eishiro Mizukoshi, Masao Hondo, Shuichi Kaneko
  • Organizer: AASLD2013
  • Place of Presentation: Washington DC, USA
  • Year and Date: 20131105-20131105
• [Presentation] Cellular immune responses for human homologue of Prp24p-derived peptides in patients with Hepatocellular Carcinoma. (2013)
  • Author(s): Kiichiro Kaji, Eishiro Mizukoshi, Tatsuya Yamashita, Kuniaki Arai, Hajime Sunagozaka, Kazumi Fushimi, Hidetoshi Nakagawa, Kazutoshi Yamada, Masaaki Kitahara, Shuichi Kaneko
  • Organizer: AASLD2013
  • Place of Presentation: Washington DC, USA
  • Year and Date: 20131104-20131104
• [Presentation] Therapeutic Efficacy and Safety of OK432-Stimulated Monocyte-Derived Dendritic Cell Injection into Hepotocellular Carcinoma after Radiofrequency Ablation. (2013)
  • Author(s): Masaaki Kitahara, Eishiro Mizukoshi, Kiichiro Kaji, Kazutoshi Yamada, Hidetoshi Nakagawa, Hajime Sunagozaka, Kuniaki Arai, Tatsuya Yamashita, Shuichi Kaneko
  • Organizer: AASLD2013
  • Place of Presentation: Washington DC, USA
  • Year and Date: 20131104-20131104
• [Presentation] Assessment of the therapeutic response of hepatocellular carcinoma treated with radiofrequency ablation : comparison of contrast-enhanced ultrasonography and computed tomography. (2013)
  • Author(s): Kuniaki Arai, Tatsuya Yamashita, Eishiro Mizukoshi, Shuichi Kaneko
  • Organizer: WFUMB 2013
  • Place of Presentation: SAO PAULO, Brazil
  • Year and Date: 20130502-20130505
• [Presentation] Contrast -enhanced ultrasonography for evaluating treatment of sorafenib in hepatocellular carcinoma. (2013)
  • Author(s): Kuniaki Arai, Tatsuya Yamashita, Eishiro Mizukoshi, Shuichi Kaneko
  • Organizer: WFUMB 2013
  • Place of Presentation: SAO PAULO, Brazil
  • Year and Date: 20130502-20130505