膵癌に対するiPS細胞由来樹状細胞を応用した革新的ペプチドワクチン療法の開発

2016 Fiscal Year Annual Research Report

• Project/Area Number: 26293308
• Research Institution: Wakayama Medical University
• Principal Investigator: 山上 裕機 和歌山県立医科大学, 医学部, 教授 (20191190)
• Co-Investigator(Kenkyū-buntansha): 清水 敦史 和歌山県立医科大学, 医学部, 学内助教 (00637910) ; 川井 学 和歌山県立医科大学, 医学部, 准教授 (40398459) ; 岡田 健一 和歌山県立医科大学, 医学部, 講師 (50407988) ; 尾島 敏康 和歌山県立医科大学, 医学部, 講師 (60448785) ; 廣野 誠子 和歌山県立医科大学, 医学部, 講師 (60468288) ; 宮澤 基樹 和歌山県立医科大学, 医学部, 助教 (90549734)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Keywords: 樹状細胞 / iPS細胞 / 膵癌免疫療法

Outline of Annual Research Achievements

本年度は倫理委員会の承認を得た後に膵癌患者を用いた実験を行った(UMIN000021105)。
1．膵癌患者からのiPS-DCの誘導：当科を受診した切除不能膵癌患者から健常人と同様のCiRA protocolでiPS細胞を誘導した。健常人と膵癌患者で得られたiPS由来DCの細胞表面マーカーの相違、抗原提示能および遊走能を指標とした成熟能の相違をFACS，IL-12 ELISA，IFN-gamma ELISAで確認した。結果、膵癌患者iPS細胞由来樹状細胞は健常人と同様に細胞表面マーカーの発現ならびに成熟能を認めた。さらに、癌抗原遺伝子の発現がないかFACSを用いたところ、WT1を1例にCEAを1例に認めた。
2．膵癌患者におけるカクテルペプチド刺激と細胞傷害性T細胞(CTL)の誘導：GMPグレードの５種類のペプチド（KIF20A, MUC16, Mesothelin, VEGFR1, R2）をiPS-DCにin vitroでパルスし、2日間培養し、ペプチド刺激後のDCの表面マーカーCD80, CD83, CD86, MHC-classI，classIIおよびCCR7, Toll-like receptor(TLR)2, 4の発現確認をflow cytometryで検討し、健常人と比較した。結果、健常人と同様のペプチドbinding affinityを認め、成熟能も同等であった。続いて、カクテルペプチドで刺激したiPS由来DCと同一患者から採取した末梢血単核球を混合培養し、ペプチド特異的なCTLを誘導した。現時点でCTL誘導能をクロムリリースアッセイならびにLDHアッセイで測定中である。本研究の第I相臨床試験への前臨床試験研究は今後は新規基盤A(17H01580)をもとに推進していく予定である。

Research Progress Status

28年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

28年度が最終年度であるため、記入しない。

Causes of Carryover

28年度が最終年度であるため、記入しない。

Expenditure Plan for Carryover Budget

28年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] Percutaneous and endoscopic gallbladder drainage for the acute cholecystitis: International multicenter comparative study by a propensity score-matched analysis. (2017)
  • Author(s): Itoi T, Takada T, Hwang TL, Endo I, Akazawa K, Miura F, Chen MF, Jan YY, Ker CG, Wang HP, Gomi H, Yokoe M, Kiriyama S, Yamaue H, Miyazaki M, Yamamoto M.
  • Journal Title: J Hepatobiliary Pancreat Sci. Volume: in press Pages: in press
  • DOI: doi: 10.1002/jhbp.454.
  • Peer Reviewed
• [Journal Article] Updated comprehensive epidemiology, microbiology, and outcomes among patients with acute cholangitis. (2017)
  • Author(s): Gomi H, Takada T, Hwang TL, Akazawa K, Mori R, Endo I, Miura F, Kiriyama S, Matsunaga N, Itoi T, Yokoe M, Chen MF, Jan YY, Ker CG, Wang HP, Wada K, Yamaue H, Miyazaki M, Yamamoto M.
  • Journal Title: J Hepatobiliary Pancreat Sci. Volume: in press Pages: in press
  • DOI: doi: 10.1002/jhbp.452.
  • Peer Reviewed
• [Journal Article] Circular stapling versus triangulating stapling for the cervical esophagogastric anastomosis after esophagectomy in patients with thoracic esophageal cancer: A prospective, randomized, controlled trial. (2017)
  • Author(s): Hayata K, Nakamori M, Nakamura M, Ojima T, Iwahashi M, Katsuda M, Tsuji T, Kato T, Kitadani J, Takeuchi A, Tabata H, Yamaue H.
  • Journal Title: Surgery. Volume: in press Pages: in press
  • DOI: doi: 10.1016/j.surg.2017.01.013.
  • Peer Reviewed
• [Journal Article] Descriptive review of acute cholecystitis: Japan-Taiwan collaborative epidemiological study. (2017)
  • Author(s): Yokoe M, Takada T, Hwang TL, Endo I, Akazawa K, Miura F, Mayumi T, Mori R, Chen MF, Jan YY, Ker CG, Wang HP, Itoi T, Gomi H, Kiriyama S, Yamaue H, Miyazaki M, Yamamoto M.
  • Journal Title: J Hepatobiliary Pancreat Sci. Volume: in press Pages: in press
  • DOI: doi: 10.1002/jhbp.450.
  • Peer Reviewed
• [Journal Article] Multicenter, randomized, open-label Phase II study comparing S-1 alternate-day oral therapy with the standard daily regimen as a first-line treatment in patients with unresectable advanced pancreatic cancer. (2017)
  • Author(s): Yamaue H, Shimizu A, Hagiwara Y, Sho M, Yanagimoto H, Nakamori S, Ueno H, Ishii H, Kitano M, Sugimori K, Maguchi H, Ohkawa S, Imaoka H, Hashimoto D, Ueda K, Nebiki H, Nagakawa T, Isayama H, Yokota I, Ohashi Y, Shirasaka T.
  • Journal Title: Cancer Chemother Pharmacol. Volume: in press Pages: in press
  • DOI: doi: 10.1007/s00280-017-3250-8.
  • Peer Reviewed
• [Journal Article] Impact of intra-abdominal absorbable sutures on surgical site infection in gastrointestinal and hepato-biliary-pancreatic surgery: results of a multicenter, randomized, prospective, phase II clinical trial. (2017)
  • Author(s): Maehara Y, Shirabe K, Kohnoe S, Emi Y, Oki E, Kakeji Y, Baba H, Ikeda M, Kobayashi M, Takayama T, Natsugoe S, Haraguchi M, Yoshida K, Terashima M, Sasako M, Yamaue H, Kokudo N, Uesaka K, Uemoto S, Kosuge T, Sawa Y, Shimada M, Doki Y, Yamamoto M, Taketomi A, Takeuchi M, Akazawa K, Yamanaka T, Shimokawa M.
  • Journal Title: Surg Today. Volume: in press Pages: in press
  • DOI: doi: 10.1007/s00595-017-1480-3.
  • Peer Reviewed
• [Journal Article] Laparoscopic Gastrojejunostomy for Patients with Unresectable Gastric Cancer with Gastric Outlet Obstruction. (2017)
  • Author(s): Ojima T, Nakamori M, Nakamura M, Katsuda M, Hayata K, Yamaue H.
  • Journal Title: J Gastrointest Surg. Volume: in press Pages: in press
  • DOI: doi: 10.1007/s11605-017-3387-0.
  • Peer Reviewed
• [Journal Article] Phase I Study of Nab-Paclitaxel plus Gemcitabine as Neoadjuvant Therapy for Borderline Resectable Pancreatic Cancer. (2017)
  • Author(s): Okada KI, Hirono S, Kawai M, Miyazawa M, Shimizu A, Kitahata Y, Ueno M, Hayami S, Yamaue H.
  • Journal Title: Anticancer Res. Volume: 37 Pages: 853-858
  • Peer Reviewed
• [Journal Article] Factors Associated With Invasive Intraductal Papillary Mucinous Carcinoma of the Pancreas. (2017)
  • Author(s): Hirono S, Kawai M, Okada KI, Miyazawa M, Shimizu A, Kitahata Y, Ueno M, Yanagisawa A, Yamaue H.
  • Journal Title: JAMA Surg. Volume: 152 Pages: e165054.
  • DOI: doi: 10.1001/jamasurg.2016.5054.
  • Peer Reviewed / Open Access
• [Journal Article] Partial clamping of the infrahepatic inferior vena cava for blood loss reduction during anatomic liver resection: A prospective, randomized, controlled trial. (2017)
  • Author(s): Ueno M, Kawai M, Hayami S, Hirono S, Okada KI, Uchiyama K, Yamaue H.
  • Journal Title: Surgery. Volume: in press Pages: in press
  • DOI: doi: 10.1016/j.surg.2016.12.010.
  • Peer Reviewed
• [Journal Article] Perineural Invasion Is Associated with Poor Survival after Preoperative Chemoradiation Therapy for Advanced Lower Rectal Cancer. (2017)
  • Author(s): Yokoyama S, Matsuda K, Watanabe T, Mitani Y, Ieda J, Iwamoto H, Hotta T, Takifuji K, Yamaue H
  • Journal Title: Dig Surg. Volume: in press Pages: in press
  • DOI: doi: 10.1159/000453591.
  • Peer Reviewed
• [Journal Article] Value of apparent diffusion coefficient prior to neoadjuvant therapy is a predictor of histologic response in patients with borderline resectable pancreatic carcinoma. (2017)
  • Author(s): Okada KI, Hirono S, Kawai M, Miyazawa M, Shimizu A, Kitahata Y, Ueno M, Hayami S, Kojima F, Yamaue H.
  • Journal Title: J Hepatobiliary Pancreat Sci. Volume: 24 Pages: 161-168
  • DOI: doi: 10.1002/jhbp.430.
  • Peer Reviewed
• [Journal Article] Phase II clinical trial using novel peptide cocktail vaccine as a postoperative adjuvant treatment for surgically resected pancreatic cancer patients. (2017)
  • Author(s): Miyazawa M, Katsuda M, Maguchi H, Katanuma A, Ishii H, Ozaka M, Yamao K, Imaoka H, Kawai M, Hirono S, Okada KI, Yamaue H.
  • Journal Title: Int J Cancer. Volume: 140 Pages: 973-982
  • DOI: doi: 10.1002/ijc.30510.
  • Peer Reviewed
• [Journal Article] Significance of preoperative fluorodeoxyglucose-positron emission tomography in prediction of tumor recurrence after liver transplantation for hepatocellular carcinoma patients: a Japanese multicenter study. (2017)
  • Author(s): Takada Y, Kaido T, Shirabe K, Nagano H, Egawa H, Yamaue H.
  • Journal Title: J Hepatobiliary Pancreat Sci. Volume: 24 Pages: 49-57
  • DOI: doi: 10.1002/jhbp.412.
  • Peer Reviewed
• [Journal Article] Whole genome sequencing discriminates hepatocellular carcinoma with intrahepatic metastasis from multi-centric tumors. (2017)
  • Author(s): Furuta M, Ueno M, Fujimoto A, Hayami S, Yamaue H.
  • Journal Title: J Hepatol. Volume: 66 Pages: 363-373
  • DOI: doi: 10.1016/j.jhep.2016.09.021.
  • Peer Reviewed
• [Journal Article] Expression of BRCA1, a factor closely associated with relapse-free survival, in patients who underwent neoadjuvant chemotherapy with docetaxel, cisplatin, and fluorouracil for squamous cell carcinoma of the esophagus. (2017)
  • Author(s): Ojima T, Nakamori M, Nakamura M, Katsuda M, Hayata K, Nakamura Y, Yamaue H.
  • Journal Title: Surg Today. Volume: 47 Pages: 65-73
  • Peer Reviewed
• [Journal Article] Clinical trials to reduce pancreatic fistula after pancreatic surgery-review of randomized controlled trials. (2016)
  • Author(s): Kitahata Y, Kawai M, Yamaue H.
  • Journal Title: Transl Gastroenterol Hepatol. Volume: 1 Pages: 4
  • DOI: doi: 10.21037/tgh.2016.03.19. eCollection 2016.
  • Peer Reviewed / Open Access
• [Journal Article] Feasibility of Endoscopic Submucosal Dissection for Submucosal-invasive Gastric Cancer and the Predictors of Residual or Recurrent Cancer. (2016)
  • Author(s): Ojima T, Takifuji K, Nakamura M, Nakamori M, Yamaue H.
  • Journal Title: Surg Laparosc Endosc Percutan Tech. Volume: 26 Pages: 401-405
  • Peer Reviewed
• [Journal Article] Clinicopathological Characteristics of Young Patients With Pancreatic Cancer: An Analysis of Data From Pancreatic Cancer Registry of Japan Pancreas Society. (2016)
  • Author(s): Eguchi H, Yamaue H, Unno M, Mizuma M, Hamada S, Igarashi H, Kuroki T, Satoi S, Shimizu Y, Tani M, Tanno S, Hirooka Y, Fujii T, Masamune A, Mizumoto K, Itoi T, Egawa S, Kodama Y, Tanaka M, Shimosegawa T
  • Journal Title: Pancreas. Volume: 45 Pages: 1411-1417
  • Peer Reviewed
• [Journal Article] Treatment Strategy for Borderline Resectable Pancreatic Cancer With Radiographic Artery Involvement. (2016)
  • Author(s): Hirono S, Kawai M, Okada KI, Miyazawa M, Shimizu A, Kitahata Y, Ueno M, Yamaue H.
  • Journal Title: Pancreas. Volume: 45 Pages: 1438-1446
  • Peer Reviewed
• [Journal Article] Impact of treatment duration of neoadjuvant FIRINOX in patients with borderline resectable pancreatic cancer: a pilot trial. (2016)
  • Author(s): Okada K, Kawai M, Hirono S, Satoi S, Yanagimoto H, Ioka T, Miyazawa M, Shimizu A, Kitahata Y, Yamaue H.
  • Journal Title: Cancer Chemother Pharmacol. Volume: 78 Pages: 719-726
  • DOI: doi: 10.1007/s00280-016-3121-8.
  • Peer Reviewed
• [Journal Article] The effects of rikkunshito on body weight loss after esophagectomy. (2016)
  • Author(s): Nakamura M, Nakamori M, Ojima T, Katsuda M, Hayata K, Iwahashi M, Yamaue H.
  • Journal Title: J Surg Res. Volume: 204 Pages: 130-138
  • DOI: doi: 10.1016/j.jss.2016.04.004.
  • Peer Reviewed
• [Journal Article] Circulating nano-particulate TLR9 agonist scouts out tumor microenvironment to release immunogenic dead tumor cells. (2016)
  • Author(s): Kitahata Y, Kanuma T, Hayashi M, Kobayashi N, Ozasa K, Kusakabe T, Temizoz B, Kuroda E, Yamaue H.
  • Journal Title: Oncotarget. Volume: 7 Pages: 48860-48869
  • DOI: doi: 10.18632/oncotarget.10379.
  • Peer Reviewed
• [Journal Article] Survival outcome of salvage hepatectomy in patients with local, recurrent hepatocellular carcinoma who underwent radiofrequency ablation as their first treatment. (2016)
  • Author(s): Ueno M, Nakai T, Hayashi M, Hirokawa F, Nagano H, Wada H, Kaibori M, Matsui K, Tanaka S, Yamaue H, Kubo S.
  • Journal Title: Surgery. Volume: 160 Pages: 661-670
  • DOI: doi: 10.1016/j.surg.2016.04.023.
  • Peer Reviewed
• [Journal Article] Long-term surveillance is necessary after operative resection for intraductal papillary mucinous neoplasm of the pancreas. (2016)
  • Author(s): Hirono S, Kawai M, Okada K, Miyazawa M, Shimizu A, Kitahata Y, Ueno M, Yanagisawa A, Yamaue H.
  • Journal Title: Surgery. Volume: 160 Pages: 306-317
  • DOI: doi: 10.1016/j.surg.2016.04.007.
  • Peer Reviewed
• [Journal Article] Grade B pancreatic fistulas do not affect survival after pancreatectomy for pancreatic cancer: A multicenter observational study. (2016)
  • Author(s): Kawai M, Murakami Y, Motoi F, Sho M, Satoi S, Matsumoto I, Honda G, Hirono S, Okada K, Unno M, Nakajima Y, Uemura K, Kwon AH, Fukumoto T, Kurata M, Yamaue H.
  • Journal Title: Surgery. Volume: 160 Pages: 293-305
  • DOI: doi: 10.1016/j.surg.2016.02.032.
  • Peer Reviewed
• [Journal Article] Whole-genome mutational landscape and characterization of noncoding and structural mutations in liver cancer. (2016)
  • Author(s): Fujimoto A, Furuta M, Totoki Y, Tsunoda T, Yamaue H.
  • Journal Title: Nat Genet. Volume: 48 Pages: 500-509
  • DOI: doi: 10.1038/ng.3547.
  • Peer Reviewed
• [Journal Article] Evaluation of the efficacy of daikenchuto (TJ -100) for the prevention of paralytic ileus after pancreaticoduodenectomy: A multicenter, double-blind, randomized, placebo-controlled trial. (2016)
  • Author(s): Okada K, Kawai M, Hirono S, Fujii T, Kodera Y, Sho M, Nakajima Y, Satoi S, Kwon AH, Shimizu Y, Ambo Y, Kondo N, Murakami Y, Ohuchida J, Eguchi H, Nagano H, Oba MS, Morita S, Sakamoto J, Yamaue H.
  • Journal Title: Surgery. Volume: 159 Pages: 1333-1341
  • DOI: doi: 10.1016/j.surg.2015.11.019.
  • Peer Reviewed
• [Journal Article] Randomized Controlled Trial of Pancreaticojejunostomy versus Stapler Closure of the Pancreatic Stump During Distal Pancreatectomy to Reduce Pancreatic Fistula. (2016)
  • Author(s): Kawai M, Hirono S, Okada K, Sho M, Nakajima Y, Eguchi H, Nagano H, Ikoma H, Morimura R, Takeda Y, Nakahira S, Suzumura K, Fujimoto J, Yamaue H.
  • Journal Title: Ann Surg. Volume: 264 Pages: 180-187
  • DOI: doi: 10.1097/SLA.0000000000001395.
  • Peer Reviewed
• [Presentation] Cancer Vaccine Therapy using iPS-derived Dendritic Cells (2016)
  • Author(s): Toshiyasu Ojima, Hiromitsu Iwamoto, Junya Kitadani, Hirotaka Tabata, Mikihito Nakamori, Masaki Nakamura, Masahiro Katsuda, Keiji Hayata, Tomoya Kato, Akihiro Takeuchi, and Hiroki Yamaue
  • Organizer: The 54 th Annual Meeting of Japanese Society of Clinical Oncology
  • Place of Presentation: 横浜
  • Year and Date: 2016-10-20 – 2016-10-22
• [Presentation] Cancer Vaccine Therapy using iPS-derived Dendritic Cells (2016)
  • Author(s): Toshiyasu Ojima, Hiromitsu Iwamoto, Junya Kitadani, Hirotaka Tabata, Mikihito Nakamori, Masaki Nakamura, Masahiro Katsuda, Keiji Hayata, Tomoya Kato, Akihiro Takeuchi, and Hiroki Yamaue
  • Organizer: The 25 th Annual Meeting of Japanese Society of Strategies for Cancer Research and Therapy
  • Place of Presentation: 千葉
  • Year and Date: 2016-06-08 – 2016-06-09