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2022 Fiscal Year Annual Research Report

Tailer made-dual directed immunotherapy for pancreatic cancer

Research Project

Project/Area Number 21H04833
Research InstitutionWakayama Medical University

Principal Investigator

山上 裕機  和歌山県立医科大学, 医学部, 学長特命教員(特別顧問) (20191190)

Co-Investigator(Kenkyū-buntansha) 川井 学  和歌山県立医科大学, 医学部, 教授 (40398459)
岡田 健一  和歌山県立医科大学, 医学部, 講師 (50407988)
勝田 将裕  和歌山県立医科大学, 医学部, 非常勤講師 (50464673)
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, 講師 (90549734)
Project Period (FY) 2021-04-05 – 2025-03-31
Keywordsがんワクチン / iPS細胞 / 樹状細胞 / ネオアンチゲン / ペプチド
Outline of Annual Research Achievements

膵癌患者iPS細胞からiPSDCsの分化誘導を行い,CTOS cell lineの確立を行った.3名の膵癌患者ドナーの末梢血単核細胞からiPS細胞の樹立を行った.iPS細胞をMatrigelコートしたdishでフィーダーレス培養を行い,5ステップ法でiPSDCsへ分化誘導を行った.膵癌患者iPSDCsとBMDCsの成熟能を比較検討するためにそれぞれの未成熟,成熟DCsにて表面マーカーの発現(CD11c,CD80,CD83,CD40,HLA-ABC,HLA-DR)をflow cytometryにて比較検討した.さらに膵癌患者iPSDCsとBMDCsのサイトカイン分泌能を比較検討するためそれぞれの未成熟,成熟DCsにてサイトカインの分泌(IFN-γ,IL-12p70, TNF-α)をELISA法にて比較検討した.膵癌患者より樹立したiPSDCsはBMDCsと同様にmaturation cocktailにて成熟し,表面マーカーであるCD11c,CD83,HLA-ABCの同程度の発現を認めた. CD80,CD40,HLA-DRについてはiPSDCsにおいて発現が低かった.さらに3名の膵癌患者ドナーよりCTOS法にて,癌スフェロイドを樹立した.ドナーより摘出した癌組織を細断したのちに,Liberase DH solution (Roche Diagnostics)を加え2時間溶解分離した.この溶解過程でsingle cellとならず細胞間接着を維持したままの細胞塊を100μmおよび40μmのcell strainerを用いて回収し,培養することで癌スフェロイドの樹立を行った.3名の膵癌ドナーの癌組織からいずれもCTOSの樹立が可能であった.腫瘍細胞マーカーであるEpCAMの高い発現を確認した.またCD45の発現は認めなかった.3名のドナーのうち1名においてCEAの高い発現を認めた.

Current Status of Research Progress
Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

膵癌切除標本からのCTOS細胞の確立に難渋していたが,培養法を改良することにより作成が可能で可能になった。また膵癌患者3ドナーから順調にiPS樹状細胞の誘導ができており,今後は研究計画通りの免疫学的解析を行うことで研究は完遂する.

Strategy for Future Research Activity

今後の研究予定は下記である.
腫瘍(CTOS)および正常組織(PBMCs)を次世代シーケンサーによりwhole exome解析し,腫瘍特異的な遺伝子変異を同定する.遺伝子変異により発生しうる変異ペプチドをin silicoにて予測する.これらの予測された変異ペプチドの中から,HLA分子との親和性が高く,RNAシーケンスにより発現量が多いと予測されたペプチドを選出し合成を行う.1ドナーから20~30種類のNeoantigen由来ペプチドを想定している。
選出した変異ペプチドに対して,ELISpot assayを用いたバリデーションスタディを行う.ELISpot assayでは腫瘍由来のRNAを導入したiPSDCs (iPSDCs-CTOS ivtRNA)により誘導されたCTLsが,変異ペプチドに対して免疫応答するかを検証する.また,選出した変異ペプチドをiPSDCsに直接パルスすることでiPSDCs-neoantigen peptideを作成し,これにより誘導したCTLsが変異ペプチドに対し免疫応答するかについても検討する.この解析で良好な結果が得られれば,膵癌ネオアンチゲンに免疫応答するiPS樹状細胞ワクチン療法の現実可能性が立証される.

  • Research Products

    (30 results)

All 2023 2022

All Journal Article (20 results) (of which Peer Reviewed: 20 results) Presentation (10 results) (of which Invited: 5 results)

  • [Journal Article] Surgical Outcomes of Pancreatectomy with Resection of the Portal Vein and/or Superior Mesenteric Vein and Jejunal Vein for Pancreatic Head Cancer2023

    • Author(s)
      Nagakawa Yuichi、Jang Jin-Young、Yamaue Hiroki、Endo Itaru、et al.
    • Journal Title

      Annals of Surgery

      Volume: 277 Pages: e1081~e1088

    • DOI

      10.1097/SLA.0000000000005330

    • Peer Reviewed
  • [Journal Article] Induced pluripotent stem cell-derived dendritic cell vaccine therapy genetically modified on the ubiquitin-proteasome system2023

    • Author(s)
      Tominaga Shinta、Ojima Toshiyasu、Miyazawa Motoki、Iwamoto Hiromitsu、Kitadani Junya、Maruoka Shimpei、Hayata Keiji、Yamaue Hiroki
    • Journal Title

      Gene Therapy

      Volume: 30 Pages: 552~559

    • DOI

      10.1038/s41434-023-00388-z

    • Peer Reviewed
  • [Journal Article] B cell receptor repertoire analysis from autopsy samples of COVID-19 patients2023

    • Author(s)
      Iwabuchi S、Tsukahara T、Okayama T、Kitabatake M、Motobayashi H、Shichino S、Imafuku T、Yamaji K、Miyamoto K、Tamura S、Ueha S、Ito T、Murata S、Kondo T、Ikeo K、Suzuki Y、Matsushima K、Kohara M、Torigoe T、Yamaue H、Hashimoto S
    • Journal Title

      Frontiers in Immunology

      Volume: 14 Pages: -

    • DOI

      10.3389/fimmu.2023.1034978

    • Peer Reviewed
  • [Journal Article] Liver Resection for Hepatocellular Carcinoma with Tumor Thrombus in the Inferior Vena Cava or Right Atrium: A Large-scale Multicenter Survey Conducted in Japan2023

    • Author(s)
      Ichida Akihiko、Kokudo Takashi、Shimada Shingo、Hatano Etsuro、Kubo Shoji、Kato Yutaro、Ishikawa Yoshiya、Mori Akira、Baba Hideo、Matsuyama Yutaka、Endo Itaru、Yamaue Hiroki、Yamamoto Masakazu、Kokudo Norihiro、Hasegawa Kiyoshi
    • Journal Title

      Annals of Surgery

      Volume: Publish Ahead of Print Pages: -

    • DOI

      10.1097/SLA.0000000000005789

    • Peer Reviewed
  • [Journal Article] Positive drain fluid culture on postoperative day 1 predicts clinically relevant pancreatic fistula in early drain removal with higher drain fluid amylase after pancreaticoduodenectomy2023

    • Author(s)
      Kawai Manabu、Okada Ken-ichi、Miyazawa Motoki、Kitahata Yuji、Motobayashi Hideki、Ueno Masaki、Hayami Shinya、Miyamoto Atsushi、Hirono Seiko、Yamaue Hiroki
    • Journal Title

      Surgery

      Volume: 173 Pages: 511~520

    • DOI

      10.1016/j.surg.2022.10.008

    • Peer Reviewed
  • [Journal Article] Impact of S‐1 adjuvant chemotherapy longer than 6?months on survival in patients with resected pancreatic cancer: a nationwide survey by the Japan Pancreas Society based on real‐world data2022

    • Author(s)
      Tomimaru Y、Eguchi H、Inoue Y、Nagakawa Y、Ohba A、Takami H、Unno M、Yamamoto T、Kawakatsu S、Hayashi T、Higuchi R、Kitagariwa H、Hatto S、Fujii T、Hirooka Y、Igarashi H、Kitano M、Kuroki T、Masamune A、Shimizu Y、Tani M、Tanno S、Tsuji Y、Yamaue H、Satoi S、Takeyama Y、et, al
    • Journal Title

      Cancer

      Volume: 129 Pages: 728~739

    • DOI

      10.1002/cncr.34580

    • Peer Reviewed
  • [Journal Article] Proteo-genomic characterization of virus-associated liver cancers reveals potential subtypes and therapeutic targets2022

    • Author(s)
      Fujita Masashi、Chen Mei-Ju May、Siwak Doris Rieko、Sasagawa Shota、Oosawa-Tatsuguchi Ayako、Arihiro Koji、Ono Atsushi、Miura Ryoichi、Maejima Kazuhiro、Aikata Hiroshi、Ueno Masaki、Hayami Shinya、Yamaue Hiroki、Chayama Kazuaki、Lee Ju-Seog、Lu Yiling、Mills Gordon B.、Liang Han、Nishizuka Satoshi S.、Nakagawa Hidewaki
    • Journal Title

      Nature Communications

      Volume: 13 Pages: -

    • DOI

      10.1038/s41467-022-34249-x

    • Peer Reviewed
  • [Journal Article] Supervised Exercise Therapy and Adjuvant Chemotherapy for Pancreatic Cancer: A Prospective, Single-Arm, Phase II Open-Label, Nonrandomized, Historically Controlled Study2022

    • Author(s)
      Okada Ken-ichi、Kouda Ken、Kawai Manabu、Hirono Seiko、Miyazawa Motoki、Kitahata Yuji、Kawanishi Makoto、Natsume Yuki、Wan Ke、Yamaue Hiroki
    • Journal Title

      Journal of the American College of Surgeons

      Volume: 235 Pages: 848~858

    • DOI

      10.1097/XCS.0000000000000408

    • Peer Reviewed
  • [Journal Article] Comprehensive analysis of full-length transcripts reveals novel splicing abnormalities and oncogenic transcripts in liver cancer2022

    • Author(s)
      Kiyose Hiroki、Nakagawa Hidewaki、Ono Atsushi、Aikata Hiroshi、Ueno Masaki、Hayami Shinya、Yamaue Hiroki、Chayama Kazuaki、Shimada Mihoko、Wong Jing Hao、Fujimoto Akihiro
    • Journal Title

      PLOS Genetics

      Volume: 18 Pages: e1010342

    • DOI

      10.1371/journal.pgen.1010342

    • Peer Reviewed
  • [Journal Article] Randomized phase <scp>III</scp> study of gemcitabine, cisplatin plus S‐1 versus gemcitabine, cisplatin for advanced biliary tract cancer ( <scp>KHBO1401</scp> ‐ <scp>MITSUBA</scp> )2022

    • Author(s)
      Ioka T、Kanai M、Kobayashi S、Sakai D、Eguchi H、Baba H、Seo S、Taketomi A、Takayama T、Yamaue H、Takahashi M、Sho M、Kamei K、Fujimoto J、Toyoda M、Shimizu J、Goto T、Shindo Y、Yoshimura K、Hatano E、Nagano H、Kansai Hepatobiliary Oncology Group (KHBO)
    • Journal Title

      Journal of Hepato-Biliary-Pancreatic Sciences

      Volume: 30 Pages: 102~110

    • DOI

      10.1002/jhbp.1219

    • Peer Reviewed
  • [Journal Article] Comparison of infectious complications after spleen preservation versus splenectomy during laparoscopic distal pancreatectomy for benign or low‐grade malignant pancreatic tumors: A multicenter, propensity score‐matched analysis2022

    • Author(s)
      Lee Woohyung、Hwang Dae Wook、Han Ho‐Seong、Han In Woong、Heo Jin Seok、Hwang Ho Kyoung、Jang Jin‐Young、Hong Taeho、Park Joon Seong、Kim Hee Joon、Jeong Chi‐Young、Yamaue H、Park Jeong‐Ik、Kim Yong Hoon、Kim Hwa Jung、Yoon Yoo‐Seok, et al.
    • Journal Title

      Journal of Hepato-Biliary-Pancreatic Sciences

      Volume: 30 Pages: 252~262

    • DOI

      10.1002/jhbp.1213

    • Peer Reviewed
  • [Journal Article] Needle tract seeding after endoscopic ultrasound‐guided tissue acquisition of pancreatic tumors: Nationwide survey in Japan2022

    • Author(s)
      Kitano M、Yoshida M、Ashida R、Kita E、Katanuma A、Itoi T、Yamaue H. et.al.
    • Journal Title

      Digestive Endoscopy

      Volume: 34 Pages: 1442~1455

    • DOI

      10.1111/den.14346

    • Peer Reviewed
  • [Journal Article] Clinical outcomes of organ‐preserving pancreatectomy for benign or low‐grade malignant pancreatic tumors: A multicenter nationwide survey in Japan2022

    • Author(s)
      Asano Yukio、Kato Hiroyuki、Arakawa Satoshi、Ito Masahiro、Nagakawa Takukazu、Nakao Akimasa、Ohta Tetsuo、Yamaue Hiroki、Yamamoto Masakazu、Satoi Sohei、Kodera Yasuhiro、Takeyama Yoshifumi、Ohtsuka Masayuki、Endo Itaru、Takada Tadahiro、Horiguchi Akihiko
    • Journal Title

      Journal of Hepato-Biliary-Pancreatic Sciences

      Volume: 29 Pages: 898~910

    • DOI

      10.1002/jhbp.1154

    • Peer Reviewed
  • [Journal Article] Prognostic significance of NY-ESO-1 antigen and PIGR expression in esophageal tumors of CHP-NY-ESO-1-vaccinated patients as adjuvant therapy2022

    • Author(s)
      Nagata Y、Kageyama S、Ishikawa T、Yamaue H、Katsuda M、Shiku H. et.al.
    • Journal Title

      Cancer Immunology, Immunotherapy

      Volume: 71 Pages: 2743~2755

    • DOI

      10.1007/s00262-022-03194-5

    • Peer Reviewed
  • [Journal Article] Immune Cells Profiles in the Different Sites of COVID-19-Affected Lung Lobes in a Single Patient2022

    • Author(s)
      Iwabuchi Sadahiro、Miyamoto Kyohei、Hatai Mayuko、Mikasa Yurina、Katsuda Masahiro、Murata Shin-ichi、Kondo Toshikazu、Yamaue Hiroki、Hashimoto Shinichi
    • Journal Title

      Frontiers in Medicine

      Volume: 9 Pages: -

    • DOI

      10.3389/fmed.2022.841170

    • Peer Reviewed
  • [Journal Article] Tumor RNA transfected DCs derived from iPS cells elicit cytotoxicity against cancer cells induced from colorectal cancer patients in vitro2022

    • Author(s)
      Maruoka Shimpei、Ojima Toshiyasu、Iwamoto Hiromitsu、Kitadani Junya、Tabata Hirotaka、Tominaga Shinta、Katsuda Masahiro、Hayata Keiji、Takeuchi Akihiro、Yamaue Hiroki
    • Journal Title

      Scientific Reports

      Volume: 12 Pages: -

    • DOI

      10.1038/s41598-022-07305-1

    • Peer Reviewed
  • [Journal Article] Laparoscopic sleeve gastrectomy for morbid obesity improves gut microbiota balance, increases colonic mucosal-associated invariant T cells and decreases circulating regulatory T cells2022

    • Author(s)
      Fukuda Naoki、Ojima Toshiyasu、Hayata Keiji、Katsuda Masahiro、Kitadani Junya、Takeuchi Akihiro、Goda Taro、Ueda Yoko、Iwakura Hiroshi、Nishi Masahiro、Yamaue Hiroki
    • Journal Title

      Surgical Endoscopy

      Volume: 36 Pages: 7312~7324

    • DOI

      10.1007/s00464-022-09122-z

    • Peer Reviewed
  • [Journal Article] Outcomes of lung metastasis from pancreatic cancer: A?nationwide multicenter analysis2022

    • Author(s)
      Homma Y、Endo I、Matsuyama R、Sho M、Mizuno S、Seyama Y、Hirano S、Aono T、Kitami C、Morita Y、Takeda Y、Yoshida K、Tani M、Kaiho T、Yamamoto Y、Aoki H、Ogawa M、Niguma T、Mataki Y、Kawasaki H、Baba H、Yokomizo H、Rikiyama T、Yamaue H、Yamamoto M
    • Journal Title

      Journal of Hepato-Biliary-Pancreatic Sciences

      Volume: 29 Pages: 552~561

    • DOI

      10.1002/jhbp.1127

    • Peer Reviewed
  • [Journal Article] Kras Gene Analysis Using Liquid-Based Cytology Specimens Predicts Therapeutic Responses and Prognosis in Patients with Pancreatic Cancer2022

    • Author(s)
      Itonaga Masahiro、Ashida Reiko、Murata Shin-Ichi、Yamashita Yasunobu、Hatamaru Keiichi、Tamura Takashi、Kawaji Yuki、Kayama Yuudai、Emori Tomoya、Kawai Manabu、Yamaue Hiroki、Matsuzaki Ibu、Nagai Hirokazu、Kinoshita Yuichi、Wan Ke、Shimokawa Toshio、Kitano Masayuki
    • Journal Title

      Cancers

      Volume: 14 Pages: 551~551

    • DOI

      10.3390/cancers14030551

    • Peer Reviewed
  • [Journal Article] Comprehensive Genomic Profiling of Neuroendocrine Carcinomas of the Gastrointestinal System2022

    • Author(s)
      Yachida S、Totoki Y、Hirono S、Hackeng Wenzel M.、Yamaue H、Brosens Lodewijk A.A.、Wood Laura D.、Hruban Ralph H.、Shibata T, et al.
    • Journal Title

      Cancer Discovery

      Volume: 12 Pages: 692~711

    • DOI

      10.1158/2159-8290.CD-21-0669

    • Peer Reviewed
  • [Presentation] Recent advances of immunotherapy for pancreatic cancer Lessons learned from basic immunology.2023

    • Author(s)
      Yamaue H, Hashimoto M
    • Organizer
      International Pancreatobiliary Meeting 2023 (IPBM 2023)
  • [Presentation] 切除可能境界・局所進行膵癌に対する外科治療の意義と位置づけ2023

    • Author(s)
      山上裕機
    • Organizer
      第123回日本外科学会定期学術集会
  • [Presentation] Treatment options for stable locally advanced pancreatic cancer after chemotherapy.2022

    • Author(s)
      Yamaue H
    • Organizer
      HBP Surgery Week 2022
    • Invited
  • [Presentation] Analysis of clinical trials evaluating complications after pancreaticoduodenectomy: a new era of pancreatic surgery.2022

    • Author(s)
      Yamaue H
    • Organizer
      The 15th International Pancreatic Cancer Conference & Commemorative
    • Invited
  • [Presentation] Recent advances for pancreatic surgery according to the results of randomized controlled trials. Lessons learned from Wakayama experiences.2022

    • Author(s)
      Yamaue H
    • Organizer
      Beijing International Hepato-Pancreato-Biliary Summit (BIHPBS 2022)
    • Invited
  • [Presentation] Pancreatectomy for advanced pancreatic cancer.2022

    • Author(s)
      Yamaue H
    • Organizer
      The 18th World Congress of Endoscopic Surgery (WCES 2022)
    • Invited
  • [Presentation] 膵体尾部切除術後の術後管理2022

    • Author(s)
      山上裕機
    • Organizer
      第49回日本膵切研究会
  • [Presentation] すべての切除可能膵癌に対して術前治療を行うか?2022

    • Author(s)
      山上裕機
    • Organizer
      第16回膵癌術前治療研究会
  • [Presentation] 高齢化社会における膵がんに対する治療戦略 -短期・長期成績を含めて-2022

    • Author(s)
      山上裕機
    • Organizer
      第60回日本癌治療学会学術集会
  • [Presentation] 膵がんに対するゲノム医療・免疫療法の最前線.2022

    • Author(s)
      山上裕機
    • Organizer
      日本放射線技術学会近畿支部主催の秋季勉強会
    • Invited

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Published: 2023-12-25  

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