Development of WT1 peptide-based immunotherapy for inoperable thoracic malignant tumors, and analysis of immunodynamics of the novel therapy

• Project/Area Number: 24591164
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Respiratory organ internal medicine
• Research Institution: Osaka University
• Principal Investigator: OKA Yoshihiro 大阪大学, 医学(系)研究科(研究院), 特任教授 (20273691)
• Co-Investigator(Kenkyū-buntansha): TAKEDA Yoshito 大阪大学, 医学(系)研究科(研究院), 助教 (40452388) ; TAKAHASHI Ryo 大阪大学, 医学(系)研究科(研究院), 助教 (10546865) ; NAGATOMO Izumi 大阪大学, 医学(系)研究科(研究院), 助教 (10570583) ; OTSUKA Tomoyuki 大阪大学, 医学部付属病院, 特任助教 (20730576)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2014: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2012: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
• Keywords: WT1 / 免疫治療 / 悪性腫瘍 / T細胞レセプター / CTL / ペプチドワクチン / 癌抗原 / Th17 / 癌ワクチン / 癌免疫療法 / ヘルパーTリンパ球 / ヘルパーペプチド / 癌免疫 / ヘルパー / 胸部悪性疾患 / 免疫療法 / がんワクチン / 肺がん

Outline of Final Research Achievements

In order to molecularly analyze cancer antigen WT1-specific immune response, we cloned a gene for T cell receptor that recognizes WT1-CTL(cytotoxic T lymphocyte) peptide with the restriction of HLA class I, and two distinct genes for those that recognize WT1-helper peptide with the restriction of HLA class II, respectively. We identified WT1-specific Th17 cells with helper function. Using the method for comprehensive analysis of gene expression profiles at a single cell level, we found that there are molecularly distinct two subpopulations in effector-memory subset of WT1-specific CTLs in peripheral blood mononuclear cells of acute myeloid leukemia patients.
We successively performed WT1 peptide-based immunotherapy (WT1 peptide vaccine) for patients with malignancies, including inoperable thoracic malignant tumors.

Research Products

• [Journal Article] Two distinct effector memory cell populations of WT1 (Wilms' tumor gene 1)-specific cytotoxic T lymphocytes in acute myeloid leukemia patients (2015)
  • Author(s): Nakae Y., Oka Y., Fujiki F., Morimoto S., Kamiya T., Takashima S., Nakata J., Nishida S., Nakajima H., Hosen N., Tsuboi A, Kyo T., Oji Y., Mizuguchi K., Kumanogoh A., Sugiyama H.
  • Journal Title: Cancer Immunology, Immunotherapy Volume: in press Issue: 7 Pages: 791-804
  • DOI: 10.1007/s00262-015-1683-7
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Transduction of a novel HLA-DRB1*04:05-restricted, WT1-specific TCR gene into human CD4+T cells confers killing activity against human leukemia cells (2015)
  • Author(s): Katsuhara A., Fujiki F., Aoyama N., Tanii S., Morimoto S., Oka Y., Tsuboi A., Nakajima H., Kondo K., Tatsumi N., Nakata J., Nakae Y., Takashima S., Nishida S., Hosen N., Sogo S., Oji Y., Sugiyama H.
  • Journal Title: Anticancer Research Volume: 35 Pages: 1251-1262
  • Peer Reviewed
• [Journal Article] Wilms tumor gene (WT1) peptide-based cancer vaccine combined with gemcitabine for patients with advanced pancreatic cancer. (2014)
  • Author(s): Nishida S, Koido S et al
  • Journal Title: J Immunother Volume: 37 Issue: 2 Pages: 105-114
  • DOI: 10.1097/cji.0000000000000020
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Maintenance of complete remission after allogeneic stem cell transplantation in leukemia patients treated with Wilms tumor 1 peptide vaccine (2013)
  • Author(s): Maeda T, Hosen N, Fukushima K, Tsuboi A, Morimoto S, Matsui T, Sata H, Fujita J, Hasegawa K, Nishida S, Nakata J, Nakae Y, Takashima S, Nakajima H, Fujiki F, Tatsumi N, Kondo T, Hino M, Oji Y, Oka Y, Kanakura Y, Kumanogoh A, Sugiyama H
  • Journal Title: Blood Cancer J Volume: 3 Issue: 8 Pages: e130-e130
  • DOI: 10.1038/bcj.2013.29
  • Peer Reviewed
• [Journal Article] A vaccine for leukemia: one step closer? Cure-oriented WT1 peptide vaccination therapy is being developed (2013)
  • Author(s): Oka Y.
  • Journal Title: Clinical Investigation Volume: 3 Issue: 5 Pages: 421-424
  • DOI: 10.4155/cli.13.27
• [Journal Article] HLA-DPB1*05: 01-restricted WT1332-specific TCR-transduced CD4+ T lymphocytes display a helper activity for WT1-specific CTL induction and a cytotoxicity against leukemia cells. (2013)
  • Author(s): Lin Y, Fujiki F, Katsuhara A, Oka Y, Tsuboi A, Aoyama N, Tanii S, Nakajima H, Tatsumi N, Morimoto S, Tamanaka T, Tachino S, Hosen N, Nishida S, Oji Y, Kumanogoh A, Sugiyama H.
  • Journal Title: J Immunother. Volume: 36（3） Issue: 3 Pages: 159-70
  • DOI: 10.1097/cji.0b013e3182873581
  • Peer Reviewed
• [Journal Article] Functional human Th17 clones with WT1-specific helper activity. (2013)
  • Author(s): Tachino S, Fujiki F, Oka Y, Tsuboi A, Morimoto S, Lin YH, Tamanaka T, Kondo K, Nakajima H, Nishida S, Hosen N, Oji Y, Kumanogoh A, Sugiyama H.
  • Journal Title: Cancer Immunol Immunother. Volume: 62（4） Issue: 4 Pages: 801-10
  • DOI: 10.1007/s00262-012-1385-3
  • Peer Reviewed
• [Journal Article] WT1 peptide immunotherapy for gynecologic malignancies resistant to conventional therapies: a phase II trial. (2013)
  • Author(s): Miyatake T.
  • Journal Title: Jounal of Cancer Research and Clinical Oncology Volume: 139 Issue: 3 Pages: 457-463
  • DOI: 10.1007/s00432-012-1348-2
  • Peer Reviewed
• [Journal Article] Vaccination with the WT-1 (Wilms’ tumor gene-1) peptide and the BCG-CWS in melanoma: A case report. (2012)
  • Author(s): Nishioka M. et al.
  • Journal Title: European Journal of Dermatology Volume: 22 Issue: 2 Pages: 258-259
  • DOI: 10.1684/ejd.2011.1619
  • Peer Reviewed
• [Journal Article] Use of (11)C-methionine PET parametric response map for monitoring WT1 immunotherapy response in recurrent malignant glioma (2012)
  • Author(s): Yasuyoshi Chiba
  • Journal Title: Journal of Neurosurgery Volume: (in press) Issue: 4 Pages: 835-842
  • DOI: 10.3171/2011.12.jns111255
  • Peer Reviewed
• [Journal Article] Recognition of a natural WT1 epitope by a modified WT1 peptide-specific T-cell receptor. (2012)
  • Author(s): Tamanaka T. et al.
  • Journal Title: Anticancer Research Volume: 32 Pages: 5201-5209
  • Peer Reviewed
• [Journal Article] Long-term WT1 peptide vaccination for patients with acute myeloid leukemia with minimal residual disease (2011)
  • Author(s): Tsuboi A, Oka Y, Kyo T, Katayama Y, Elisseeva OA, Kawakami M, Nishida S, Morimoto S, Murao A, Nakajima H, Hosen N, Oji Y, Sugiyama H.
  • Journal Title: Leukemia Volume: 2011(in press) Issue: 6 Pages: 1410-1413
  • DOI: 10.1038/leu.2011.343
  • Peer Reviewed
• [Presentation] WT1ペプチドを用いたがんワクチン療法 (2015)
  • Author(s): 岡 芳弘
  • Organizer: 第13回日本組織適合性学会近畿地方会
  • Place of Presentation: 大阪市
  • Year and Date: 2015-02-07
  • Invited
• [Presentation] 悪性神経膠腫に対するWT1ペプチドワクチン療法の効果増強の試み (2014)
  • Author(s): 坪井昭博、橋本直哉、香川尚己、泉本修一、岡 芳弘、尾路祐介、森本創世子、保仙直毅、西田純幸、中田 潤、中江吉希、吉峰俊樹、杉山治夫
  • Organizer: 第27回日本バイオセラピィ学会学術集会総会
  • Place of Presentation: 大阪市
  • Year and Date: 2014-12-04
• [Presentation] WT1 peptide-based immunotherapy combined with Temozoromide for patients with newly diagnosed glioblastoma (2014)
  • Author(s): Tsuboi A., Hashimoto N., Kagawa N., Izumoto S., Oka Y., Oji Y., Hosen N., Nishida S., Morimoto S., Yoshimine T., Sugiyama H.
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: 横浜市
  • Year and Date: 2014-09-25
• [Presentation] 再発悪性神経膠芽腫を対象としたWT1キラーペプチドとWT1ヘルパーペプチドを用いた免疫療法 第１相試験 (2014)
  • Author(s): 坪井昭博、橋本直哉、岡 芳弘、森本創世子、尾路祐介、保仙直毅、西田純幸、中田 潤、中江吉希、中島博子、吉峰俊樹、杉山治夫
  • Organizer: 第18回日本がん免疫学会総会
  • Place of Presentation: 松山市
  • Year and Date: 2014-07-31
• [Presentation] 初発膠芽腫に対するテモゾロミド併用WT1ペプチドワクチン療法
  • Author(s): 坪井昭博 et al
  • Organizer: 第26回日本バイオセラピィ学会学術集会総会
  • Place of Presentation: 盛岡（いわて県民情報交流センター アティーナ）
• [Presentation] Clinical study of WT1 peptide vaccination for pediatric leukemia after stem cell transplantation
  • Author(s): 橋井佳子 et al
  • Organizer: 第75回日本血液学会学術集会
  • Place of Presentation: 札幌（ロイトン札幌・さっぽろ芸文館）
• [Presentation] WT1 based immunotherapy for pediatric patients with solid malignant tumor: phase I/II trial
  • Author(s): 橋井佳子 et al
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: 横浜（パシフィコ横浜）
• [Presentation] HLA-DPB1*05:01拘束性WT1特異的TCRを導入されたCD4+T細胞はヘルパー活性と細胞障害活性を有する
  • Author(s): 藤木文博 et al
  • Organizer: 第17回がん免疫学会総会
  • Place of Presentation: 宇部（ANAクラウンプラザ宇部）
• [Presentation] 初発悪性神経膠腫を対象としたテモゾロミド併用WT1ペプチドワクチン第I相臨床試験
  • Author(s): 坪井昭博ら
  • Organizer: 第１６回日本がん免疫学会総会
  • Place of Presentation: 北海道大学学術交流会館（札幌）
• [Presentation] WT1 immunohistochemical staining and evaluation of WT1 positivity in solid cancers.
  • Author(s): 尾路祐介ら
  • Organizer: 第７１回日本癌学会学術総会
  • Place of Presentation: 札幌市教育文化会館（札幌）
• [Presentation] 再発ハイリスク同種造血幹細胞移植後患者に対するWT1ペプチドワクチン第１相臨床試験.
  • Author(s): 保仙直毅ら
  • Organizer: 第７４回日本血液学会学術総会
  • Place of Presentation: 国立京都国際会館（京都）
• [Presentation] がん抗原ペプチドを用いたワクチン治療の原理・現況・将来展望 －WT1ペプチドがんワクチンをそのモデルとして－
  • Author(s): 岡 芳弘ら
  • Organizer: 第11回日本組織適合性学会近畿地方会
  • Place of Presentation: 参天製薬株式会社（大阪）
  • Invited