Novel pancreatic cancer treatment combining immune suppression mechanism and autophagy induction virus therapy

2018 Fiscal Year Annual Research Report

• Project/Area Number: 16K15623
• 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): 中森 幹人 和歌山県立医科大学, 医学部, 准教授 (10322372) ; 川井 学 和歌山県立医科大学, 医学部, 准教授 (40398459) ; 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)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: 膵癌 / 免疫療法 / ウイルス療法 / iPS細胞 / 樹状細胞

Outline of Annual Research Achievements

本研究「免疫抑制機構克服とオートファジー誘導ウイルス療法を併用した新規膵癌治療の開発」で平成30年度は主に健常人ならびに膵癌患者からのiPS細胞由来樹状細胞(iPS-DC)の誘導を行った．
健常人3名のPBMCよりセンダイウイルスベクターを用いて山中4因子を導入し，iPS細胞を樹立した．その後LC3遺伝子を導入した．このiPS細胞を5 step法を用いて各種サイトカインを添加しながら，胚細胞様細胞塊，単球　樹状細胞へと分化誘導し，成熟化した。細胞表面マーカーおよびIFN-g, IL-12の産生能をチェックし，成熟DCへの分化誘導を確認した。同様に膵癌手術症例3名より，膵癌切除標本を用いて，medium希釈法を用いて，cell line化を試みたが，樹立不可能であった．そのため，CTOS法を用いて，3D培養を行い，cell line化に成功，その細胞におけるPD-1 PD-L1発現を確認した．その後，同様に膵癌患者3名のPBMCより，iPS-DCを5 step法にて分化誘導した．細胞表面マーカー (CD11b CD11c CD40 CD80 CD83 MHC-class I/II CCR7)の確認ならびに，3Dチャンバーを用いた遊走能の確認を行い，健常人と相違ないことを確認した．

Research Products

• [Journal Article] Robotic radical lymphadenectomy without touching the pancreas during gastrectomy for gastric cancer. (2019)
  • Author(s): Ojima T, Nakamura M, Nakamori M, Hayata K, Katsuda M, Maruoka S, Yamaue H.
  • Journal Title: Medicine Volume: 98 Pages: e15091
  • DOI: 10.1097/MD.0000000000015091.
  • Peer Reviewed / Open Access
• [Journal Article] Decreased serum carbohydrate antigen 19-9 levels after neoadjuvant therapy predict a better prognosis for patients with pancreatic adenocarcinoma: a multicenter case-control study of 240 patients. (2019)
  • Author(s): Aoki S, Motoi F, Murakami Y, Sho M, Satoi S, Honda G, Uemura K, Okada KI, Matsumoto I, Nagai M, Yanagimoto H, Kurata M, Fukumoto T, Mizuma M, Yamaue H, Unno M; Multicenter Study Group of Pancreatobiliary Surgery (MSG-PBS).
  • Journal Title: BMC Cancer. Volume: 19 Pages: 252
  • DOI: 10.1186/s12885-019-5460-4.
  • Peer Reviewed / Open Access
• [Journal Article] Triplet chemotherapy with docetaxel, cisplatin and S-1 for unresectable advanced squamous cell carcinoma of the esophagus: phase I/II trial results. (2019)
  • Author(s): Ojima T, Nakamura M, Nakamori M, Katsuda M, Hayata K, Kitadani J, Maruoka S, Shimokawa T, Yamaue H.
  • Journal Title: Oncotarget. Volume: 10 Pages: 847-855
  • DOI: 10.18632/oncotarget.26614.
  • Peer Reviewed / Open Access
• [Journal Article] Triangulating stapling vs functional end-to-end stapling for cervical esophagogastric anastomosis after esophagectomy for thoracic esophageal cancer: study protocol for a randomized controlled trial. (2019)
  • Author(s): Tsuji T, Ojima T, Nakamori M, Nakamura M, Katsuda M, Hayata K, Kitadani J, Maruoka S, Shimokawa T, Yamaue H.
  • Journal Title: Trials. Volume: 20 Pages: 83
  • DOI: 10.1186/s13063-019-3201-2.
  • Peer Reviewed / Open Access
• [Journal Article] Concomitant Use of Indocyanine Green Fluorescence Imaging and Interventional Radiology for Detection of Liver Segments During Laparoscopic Anatomical Liver Resection: Pilot Feasibility Study. (2019)
  • Author(s): Ueno M, Hayami S, Sonomura T, Kawai M, Hirono S, Okada KI, Tanaka R, Yamaue H.
  • Journal Title: Surg Laparosc Endosc Percutan Tech. Volume: in press Pages: in press
  • DOI: 10.1097/SLE.0000000000000631.
  • Peer Reviewed
• [Journal Article] Outcomes and Risk Score for Distal Pancreatectomy with Celiac Axis Resection (DP-CAR): An International Multicenter Analysis. (2019)
  • Author(s): Klompmaker S，Peters NA，van Hilst J，Bassi C， Boggi U， Yamaue H, Wolfgang CL, Hogg ME, Besselink MG; E-AHPBA DP-CAR study group.
  • Journal Title: Ann Surg Oncol. Volume: 26 Pages: 772-781.
  • DOI: 10.1245/s10434-018-07101-0.
  • Peer Reviewed
• [Journal Article] Clinical Impact of Neoadjuvant Chemotherapy and Chemoradiotherapy in Borderline Resectable Pancreatic Cancer: Analysis of 884 Patients at Facilities Specializing in Pancreatic Surgery. (2019)
  • Author(s): Nagakawa Y, Sahara Y, Hosokawa Y, Murakami Y, Yamaue H, Satoi S, Unno M, Isaji S, Endo I, Sho M, Fujii T, Takishita C, Hijikata Y, Suzuki S, Kawachi S, Katsumata K, Ohta T, Nagakawa T, Tsuchida A.
  • Journal Title: Ann Surg Oncol. Volume: in press Pages: in press
  • DOI: 10.1245/s10434-018-07131-8.
  • Peer Reviewed
• [Journal Article] Randomized phase II/III trial of neoadjuvant chemotherapy with gemcitabine and S-1 versus upfront surgery for resectable pancreatic cancer (Prep-02/JSAP05). (2019)
  • Author(s): Motoi F, Kosuge T, Ueno H, Yamaue H, Satoi S, Sho M, Honda G, Matsumoto I, Wada K, Furuse J, Matsuyama Y, Unno M; Study Group of Preoperative Therapy for Pancreatic Cancer (Prep) and Japanese Study Group of Adjuvant Therapy for Pancreatic cancer (JSAP).
  • Journal Title: Jpn J Clin Oncol. Volume: 49 Pages: 190-194.
  • DOI: 10.1093/jjco/hyy190.
  • Peer Reviewed
• [Journal Article] Robotic complete lymphadenectomy at the splenic hilum during total gastrectomy for advanced gastric cancer (with video). (2019)
  • Author(s): Ojima T, Hayata K, Yamaue H.
  • Journal Title: J Visc Surg. Volume: in press Pages: in press
  • DOI: 10.1016/j.jviscsurg.2018.12.005.
  • Peer Reviewed
• [Journal Article] Inhibitory functions of PD-L1 and PD-L2 in the regulation of anti-tumor immunity in murine tumor microenvironment. (2019)
  • Author(s): Umezu D, Okada N, Sakoda Y, Adachi K, Ojima T, Yamaue H, Eto M, Tamada K.
  • Journal Title: Cancer Immunol Immunother. Volume: 68 Pages: 201-211
  • DOI: 10.1007/s00262-018-2263-4.
  • Peer Reviewed
• [Journal Article] Sustained Elevation of Postoperative Serum Level of Carbohydrate Antigen 19-9 is High-Risk Stigmata for Primary Hepatic Recurrence in Patients with Curatively Resected Pancreatic Adenocarcinoma. (2019)
  • Author(s): Motoi F, Murakami Y, Okada KI, Matsumoto I, Uemura K, Satoi S, Sho M, Honda G, Fukumoto T, Yanagimoto H, Kinoshita S, Kurata M, Aoki S, Mizuma M, Yamaue H, Unno M; Multicenter Study Group of Pancreatobiliary Surgery (MSG-PBS).
  • Journal Title: World J Surg. Volume: 43 Pages: 634-641.
  • DOI: 10.1007/s00268-018-4814-4.
  • Peer Reviewed
• [Journal Article] Conversion Surgery for Gastric Cancer with Peritoneal Metastasis Based on the Diagnosis of Second-Look Staging Laparoscopy. (2019)
  • Author(s): Nakamura M, Ojima T, Nakamori M, Katsuda M, Tsuji T, Hayata K, Kato T, Yamaue H.
  • Journal Title: J Gastrointest Surg. Volume: in press Pages: in press
  • DOI: 10.1007/s11605-018-3983-7.
  • Peer Reviewed
• [Journal Article] Optimal Timing of Removal of Epidural and Urethral Catheters to Avoid Postoperative Urinary Retention Undergoing Abdominal Surgery. (2019)
  • Author(s): Hayami S, Ueno M, Kawai M, Kuriyama T, Kawamata T, Yamaue H.
  • Journal Title: Dig Surg. Volume: 36 Pages: 261-265.
  • DOI: 10.1159/000490199.
  • Peer Reviewed
• [Journal Article] Modified Blumgart Mattress Suture Versus Conventional Interrupted Suture in Pancreaticojejunostomy During Pancreaticoduodenectomy: Randomized Controlled Trial. (2019)
  • Author(s): Hirono S, Kawai M, Okada KI, Miyazawa M, Kitahata Y, Hayami S, Ueno M, Yamaue H.
  • Journal Title: Ann Surg. Volume: 269 Pages: 243-251.
  • DOI: 10.1097/SLA.0000000000002802.
  • Peer Reviewed
• [Journal Article] MAPLE-PD trial (Mesenteric Approach vs. Conventional Approach for Pancreatic Cancer during Pancreaticoduodenectomy): study protocol for a multicenter randomized controlled trial of 354 patients with pancreatic ductal adenocarcinoma. (2018)
  • Author(s): Hirono S, Kawai M, Okada KI, Fujii T, Sho M, Satoi S, Amano R, Eguchi H, Mataki Y, Nakamura M, Matsumoto I, Baba H, Tani M, Kawabata Y, Nagakawa Y, Yamada S, Murakami Y, Shimokawa T, Yamaue H.
  • Journal Title: Trials. Volume: 19 Pages: 613
  • DOI: 10.1186/s13063-018-3002-z.
  • Peer Reviewed / Open Access
• [Journal Article] Overexpression of KDM5B/JARID1B is associated with poor prognosis in hepatocellular carcinoma. (2018)
  • Author(s): Shigekawa Y, Hayami S, Ueno M, Miyamoto A, Suzaki N, Kawai M, Hirono S, Okada KI, Hamamoto R, Yamaue H.
  • Journal Title: Oncotarget Volume: 9 Pages: 34320-34335.
  • DOI: 10.18632/oncotarget.26144. e
  • Peer Reviewed
• [Journal Article] Transition of serum cytokines following pancreaticoduodenectomy: A subsidiary study of JAPAN-PD. (2018)
  • Author(s): Maeda H, Okada KI, Fujii T, Oba MS, Kawai M, Hirono S, Kodera Y, Sho M, Akahori T, Shimizu Y, Ambo Y, Kondo N, Murakami Y, Ohuchida J, Eguchi H, Nagano H, Sakamoto J, Yamaue H.
  • Journal Title: Oncol Lett. Volume: 16 Pages: 6847-6853.
  • DOI: 10.3892/ol.2018.9422.
  • Peer Reviewed / Open Access
• [Journal Article] Outcomes of 1,639 hepatectomies for non-colorectal non-neuroendocrine liver metastases: a multicenter analysis. (2018)
  • Author(s): Sano K, Yamamoto M, Mimura T, Endo I, Nakamori S, Konishi M, Miyazaki M, Wakai T, Nagino M, Kubota K, Unno M, Sata N, Yamamoto J, Yamaue H, Takada T; Japanese Society of Hepato-Biliary-Pancreatic Surgery.
  • Journal Title: J Hepatobiliary Pancreat Sci. Volume: 25 Pages: 465-475.
  • DOI: 10.1002/jhbp.587.
  • Peer Reviewed
• [Journal Article] Learning curve and surgical factors influencing the surgical outcomes during the initial experience with laparoscopic pancreaticoduodenectomy. (2018)
  • Author(s): Nagakawa Y, Nakamura Y, Honda G, Gotoh Y, Ohtsuka T, Ban D, Nakata K, Sahara Y, Velasquez VVDM, Takaori K, Misawa T, Kuroki T, Kawai M, Morikawa T, Yamaue H, Tanabe M, Mou Y, Lee WJ, Shrikhande SV, Conrad C, Han HS, Tang CN, Palanivelu C, Kooby DA, Asbun HJ, Wakabayashi G, Tsuchida A, Takada T, Yamamoto M, Nakamura M.
  • Journal Title: J Hepatobiliary Pancreat Sci. Volume: 25 Pages: 498-507.
  • DOI: 10.1002/jhbp.586.
  • Peer Reviewed
• [Journal Article] Intensive perioperative rehabilitation improves surgical outcomes after pancreaticoduodenectomy. (2018)
  • Author(s): Kitahata Y, Hirono S, Kawai M, Okada KI, Miyazawa M, Shimizu A, Kobayashi R, Ueno M, Hayami S, Shimokawa T, Kouda K, Tajima F, Yamaue H.
  • Journal Title: Langenbecks Arch Surg. Volume: 403 Pages: 711-718.
  • DOI: 10.1007/s00423-018-1710-1.
  • Peer Reviewed
• [Journal Article] Endoscopic treatment of esophageal fistulas after esophagectomy with injection of an alpha-cyanoacrylate monomer: a phase II study. (2018)
  • Author(s): Ojima T, Nakamura M, Nakamori M, Katsuda M, Hayata K, Tsuji T, Maruoka S, Yamaue H.
  • Journal Title: Endosc Int Open. Volume: 6 Pages: E1093-E1099.
  • DOI: 10.1055/a-0581-9005.
  • Peer Reviewed / Open Access
• [Journal Article] Neoadjuvant Chemotherapy with Docetaxel, Cisplatin and S-1 for Resectable Advanced Esophageal Cancer. (2018)
  • Author(s): Hayata K, Ojima T, Nakamori M, Nakamura M, Katsuda M, Kitadani J, Takeuchi A, Tabata H, Maruoka S, Yamaue H.
  • Journal Title: Anticancer Res. Volume: 38 Pages: 5267-5273.
  • DOI: 10.21873/anticanres.12852.
  • Peer Reviewed
• [Journal Article] Reinforced Stapling Technique for Reconstruction After Laparoscopic Distal Gastrectomy. (2018)
  • Author(s): Ojima T, Nakamura M, Hayata K, Nakamori M, Yamaue H.
  • Journal Title: Surg Laparosc Endosc Percutan Tech. Volume: 28 Pages: 334-336.
  • DOI: 10.1097/SLE.0000000000000570.
  • Peer Reviewed
• [Journal Article] Identification of a novel HLA-A24-restricted cytotoxic T lymphocyte epitope peptide derived from mesothelin in pancreatic cancer. (2018)
  • Author(s): Tsukagoshi M, Wada S, Hirono S, Yoshida S, Yada E, Sasada T, Shirabe K, Kuwano H, Yamaue H.
  • Journal Title: Oncotarget. Volume: 9 Pages: 31448-31458.
  • DOI: 10.18632/oncotarget.25837.
  • Peer Reviewed / Open Access
• [Journal Article] Difficulty scoring system in laparoscopic distal pancreatectomy. (2018)
  • Author(s): Ohtsuka T, Ban D, Nakamura Y, Nagakawa Y, Tanabe M, Gotoh Y, Velasquez VVDM, Nakata K, Sahara Y, Takaori K, Honda G, Misawa T, Kawai M, Yamaue H, Morikawa T, Kuroki T, Mou Y, Lee WJ, Shrikhande SV, Tang CN, Conrad C, Han HS, Palanivelu C, Asbun HJ, Kooby DA, Wakabayashi G, Takada T, Yamamoto M, Nakamura M.
  • Journal Title: J Hepatobiliary Pancreat Sci. Volume: 25 Pages: 489-497.
  • DOI: 10.1002/jhbp.578.
  • Peer Reviewed
• [Journal Article] Distal Pancreatectomy with Celiac Axis Resection (DP-CAR) for Pancreatic Cancer. How I do It. (2018)
  • Author(s): Klompmaker S, Boggi U, Hackert T, Salvia R, Weiss M, Yamaue H, Zeh HJ, Besselink MG.
  • Journal Title: J Gastrointest Surg. Volume: 22 Pages: 1804-1810.
  • DOI: 10.1007/s11605-018-3894-7.
  • Peer Reviewed
• [Journal Article] Significance of hepatic resection and adjuvant hepatic arterial infusion chemotherapy for hepatocellular carcinoma with portal vein tumor thrombus in the first branch of portal vein and the main portal trunk: a project study for hepatic surgery of the Japanese Society of Hepato-Biliary-Pancreatic Surgery. (2018)
  • Author(s): Hatano E, Uemoto S, Yamaue H, Yamamoto M; Japanese Society of Hepato-Biliary-Pancreatic Surgery.
  • Journal Title: J Hepatobiliary Pancreat Sci. Volume: 25 Pages: 395-402.
  • DOI: 10.1002/jhbp.574.
  • Peer Reviewed
• [Journal Article] Resection for recurrent pancreatic cancer in the remnant pancreas after pancreatectomy is clinically promising: Results of a project study for pancreatic surgery by the Japanese Society of Hepato-Biliary-Pancreatic Surgery. (2018)
  • Author(s): Yamada S, Kobayashi A, Nakamori S, Baba H, Yamamoto M, Yamaue H, Fujii T.
  • Journal Title: Surgery. Volume: 164 Pages: 1049-1056.
  • DOI: 10.1016/j.surg.2018.05.050.
  • Peer Reviewed
• [Journal Article] Robotic versus laparoscopic gastrectomy with lymph node dissection for gastric cancer: study protocol for a randomized controlled trial. (2018)
  • Author(s): Ojima T, Nakamura M, Nakamori M, Hayata K, Katsuda M, Kitadani J, Maruoka S, Shimokawa T, Yamaue H.
  • Journal Title: Trials. Volume: 19 Pages: 409.
  • DOI: 10.1186/s13063-018-2810-5.
  • Peer Reviewed / Open Access
• [Journal Article] Splenic vein resection together with the pancreatic parenchyma versus separated resection after isolation of the parenchyma during distal pancreatectomy (COSMOS-DP trial): study protocol for a randomised controlled trial. (2018)
  • Author(s): Yamada S, Fujii T, Kawai M, Shimokawa T, Nakamura M, Murakami Y, Satoi S, Eguchi H, Nagakawa Y, Kodera Y, Yamaue H.
  • Journal Title: Trials. Volume: 19 Pages: 369.
  • DOI: 10.1186/s13063-018-2756-7.
  • Peer Reviewed / Open Access
• [Journal Article] Minimally invasive preservation versus splenectomy during distal pancreatectomy: a systematic review and meta-analysis. (2018)
  • Author(s): Nakata K, Yamaue H, Morikawa T, Kuroki T, Mou Y, Lee WJ, Shrikhande SV, Tang CN, Conrad C, Han HS, Chinnusamy P, Asbun HJ, Kooby DA, Wakabayashi G, Takada T, Yamamoto M, Nakamura M.
  • Journal Title: J Hepatobiliary Pancreat Sci. Volume: 25 Pages: 476-488.
  • DOI: 10.1002/jhbp.569.
  • Peer Reviewed
• [Journal Article] Clinical impact of developing better practices at the institutional level on surgical outcomes after distal pancreatectomy in 1515 patients: Domestic audit of the Japanese Society of Pancreatic Surgery. (2018)
  • Author(s): Satoi S, Yamamoto T, Motoi F, Matsumoto I, Yoshitomi H, Amano R, Tahara M, Murakami Y, Arimitsu H, Hirono S, Sho M, Ryota H, Ohtsuka M, Unno M, Takeyama Y, Yamaue H.
  • Journal Title: Ann Gastroenterol Surg. Volume: 25 Pages: 212-219.
  • DOI: 10.1002/ags3.12066.
  • Peer Reviewed
• [Journal Article] Characterization of HBV integration patterns and timing in liver cancer and HBV-infected livers. (2018)
  • Author(s): Furuta M, Tanaka H, Shiraishi Y, Unida T, Imamura M, Fujimoto A, Fujita M, Sasaki-Oku A, Maejima K, Nakano K, Kawakami Y, Arihiro K, Aikata H, Ueno M, Hayami S, Ariizumi SI, Yamamoto M, Gotoh K, Ohdan H, Yamaue H, Miyano S, Chayama K, Nakagawa H.
  • Journal Title: Oncotarget. Volume: 9 Pages: 25075-25088.
  • DOI: 10.18632/oncotarget.25308.
  • Peer Reviewed / Open Access
• [Journal Article] Phase I/II Trial of Chemotherapy with Docetaxel, Cisplatin, and S-1 for Unresectable Advanced Squamous Cell Carcinoma of the Esophagus. (2018)
  • Author(s): Ojima T, Nakamura M, Nakamori M, Katsuda M, Hayata K, Maruoka S, Shimokawa T, Yamaue H.
  • Journal Title: Oncology. Volume: 95 Pages: 116-120.
  • DOI: 10.1159/000488861.
  • Peer Reviewed
• [Journal Article] Fundoplication with 180-Degree Wrap During Esophagogastrostomy After Robotic Proximal Gastrectomy for Early Gastric Cancer. (2018)
  • Author(s): Ojima T, Nakamori M, Nakamura M, Hayata K, Maruoka S, Yamaue H.
  • Journal Title: J Gastrointest Surg. Volume: 22 Pages: 1475-1476.
  • DOI: 10.1007/s11605-018-3765-2.
  • Peer Reviewed
• [Journal Article] A phase I/Ib study of OTSGC-A24 combined peptide vaccine in advanced gastric cancer. (2018)
  • Author(s): Sundar R, Rha SY, Yamaue H, Katsuda M, Kono K, Kim HS, Kim C, Mimura K, Kua LF, Yong WP.
  • Journal Title: BMC Cancer. Volume: 18 Pages: 332.
  • DOI: 10.1186/s12885-018-4234-8.
  • Peer Reviewed / Open Access
• [Journal Article] Cancer Vaccine Therapy Using Carcinoembryonic Antigen - expressing Dendritic Cells generated from Induced Pluripotent Stem Cells. (2018)
  • Author(s): Kitadani J, Ojima T, Iwamoto H, Tabata H, Nakamori M, Nakamura M, Hayata K, Katsuda M, Miyajima M, Yamaue H.
  • Journal Title: Sci Rep. Volume: 8 Pages: 4569
  • DOI: 10.1038/s41598-018-23120-z.
  • Peer Reviewed / Open Access
• [Presentation] iPS細胞由来樹状細胞を用いたテーラーメード癌ワクチン療法 (2018)
  • Author(s): 尾島敏康 岩本博光 北谷純也 田端宏尭 出口真彰 中森幹人 中村公紀 勝田将裕 早田啓治 丸岡慎平 山上裕機
  • Organizer: 第56回日本癌治療学会学術集会
• [Presentation] iPS細胞由来樹状細胞を用いたテーラーメード癌ワクチン療法の現状と未来 (2018)
  • Author(s): 尾島敏康 岩本博光 北谷純也 田端宏尭 出口真彰 中森幹人 中村公紀 勝田将裕 早田啓治 丸岡慎平 山上裕機
  • Organizer: 第31回日本バイオセラピー学会学術集会