Establishment of a mouse leukemia model and the exploring the way to enhance the anti-leukemia immunity using this mouse leukemia model.

• Project/Area Number: 15K19550
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Hematology
• Research Institution: Osaka University
• Principal Investigator: Jun Nakata 大阪大学, 医学系研究科, 寄附講座助教 (90528952)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2017: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2016: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: マウス白血病モデル / 癌免疫 / 癌ワクチン / WT1 / 併用療法 / ヘルパーペプチド / 白血病 / WT1ワクチン / 急性骨髄性白血病 / 癌免疫療法 / 腫瘍免疫

Outline of Final Research Achievements

We analyzed the immunological features of patients in Phase 2 clinical study of WT1 peptide vaccination for AML patients after chemotherapy. We found that the frequencies of WT1 specific CTLs were higher in good responders than in poor responders. Also we clarified the clonality of these CTLs and reported the results. Next, we established a new mouse leukemia model by transducing the human lukememia gene 'MLL/AF9' into the c-kit+ BM cells of B6 mice. By using this mouse leukeia model, we found that the helper WT1 peptide could enhance and prolong the anti-leukemia effect of WT1 CTL peptide vaccination and that combination peptide vaccination therapy could lead the better clinical outcome than the CTL peptide vaccination alone. WT1 specific CTLs in combination peptide vaccination were not exhausted at least whithin 3 months, so checkpoint blockade therapy showed no clinical benefit when we used it combined with the combination peptide vaccination therapy.

Research Products

• [Journal Article] Wilms tumour 1 peptide vaccine as a cure-oriented post-chemotherapy strategy for patients with acute myeloid leukaemia at high risk of relapse. (2017)
  • Author(s): Nakata J, Nakae Y, Kawakami M, Morimoto S, Motooka D, Hosen N, Fujiki F, Nakajima H, Hasegawa K, Nishida S, Tsuboi A, Oji Y, Oka Y, Kumanogoh A, Sugiyama H.
  • Journal Title: Br J Haematol. Volume: XX Issue: 2 Pages: 287-290
  • DOI: 10.1111/bjh.14768
  • Peer Reviewed / Open Access
• [Journal Article] Association of WT1 IgG antibody against WT1 peptide with prolonged survival in glioblastoma multiforme patients vaccinated with WT1 peptide. (2016)
  • Author(s): Oji Y, Hashimoto N, Tsuboi A, Murakami Y, Iwai M, Kagawa N, Chiba Y, Izumoto S, Elisseeva O, Ichinohasama R, Sakamoto J, Morita S, Nakajima H, Takashima S, Nakae Y, Nakata J, Kawakami M, Nishida S, Hosen N, Fujiki F, Morimoto S, Adachi M, Iwamoto M, Oka Y, Yoshimine T, Sugiyama H.
  • Journal Title: Int J Cancer. Volume: 139 Issue: 6 Pages: 1391-401
  • DOI: 10.1002/ijc.30182
  • Peer Reviewed / Open Access
• [Journal Article] Syndecan-4 as a biomarker to predict clinical outcome for glioblastoma multiforme treated with WT1 peptide vaccine (2016)
  • Author(s): Takashima S, Oka Y, Fujiki F, Morimoto S, Nakajima H, Nakae Y, Nakata J, Nishida S, Hosen N, Tatsumi N, Mizuguchi K, Hashimoto N, Oji Y, Tsuboi A, Kumanogoh A, Sugiyama H
  • Journal Title: Future Sci OA Volume: FSO96 Issue: 4
  • DOI: 10.4155/fsoa-2015-0008
  • Peer Reviewed / Open Access
• [Journal Article] An essential role of the avidity of T-cell receptor in differentiation of self-antigen-reactive CD8+ T cells (2016)
  • Author(s): Kondo K, Fujiki F, Nakajima H, Yatsukawa E, Morimoto S, Tatsumi N, Nishida S, Nakata J, Oka Y, Tsuboi A, Hosen N, Oji Y, Sugiyama H
  • Journal Title: Journal of Immunotherapy Volume: 39 Issue: 3 Pages: 127-139
  • DOI: 10.1097/cji.0000000000000114
  • Peer Reviewed / Open Access
• [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
• [Presentation] WT1 vaccine therapy against AML: combination strategy for the next step. (2018)
  • Author(s): Nakata J, Nakajima H, Nakae Y, Mizutani Y, Imafuku K, Morimoto S, Fujiki F, Kawakami Y, Nishida S, Hosen N, Tsuboi A, Oji Y, Oka Y, Kumanogoh A, Sugiyama H
  • Organizer: Cancer Immunotherapy: Combinations (C5) in Keystone Symposia
  • Int'l Joint Research
• [Presentation] 急性骨髄性白血病に対するWT1ワクチン療法の進捗 (2017)
  • Author(s): 中田潤、中江吉希、川上学、森本創世子、元岡大祐、水谷陽、保仙直毅、藤木文博、中島博子、長谷川加奈、西田純幸、坪井昭博、尾路祐介、岡芳弘、杉山治夫
  • Organizer: 第9回 血液疾患免疫療法学会学術集会
• [Presentation] WT1 peptide vaccination could be a maintenance therapy for AML patients with high risk of relapse (2016)
  • Author(s): 中田潤
  • Organizer: 日本血液学会
  • Place of Presentation: パシフィコ横浜
• [Presentation] 急性骨髄性白血病に対するWT1ワクチン療法 (2016)
  • Author(s): 中田潤
  • Organizer: 血液疾患免疫療法学会
  • Place of Presentation: 北海道大学医学部学友会館「フラテ」
• [Presentation] WT1 peptide-based immunotherapy as post-chemotherapy treatment in adult AML patients at high risk of relapse (2015)
  • Author(s): Jun Nakata, Yoshiki Nakae, Manabu Kawakami, Soyoko Morimoto, Fumihiro Fujiki, Hiroko Nakajima, Sumiyuki Nishida, Naoki Hosen, Akihiro Tsuboi, Yuske Oji, Yoshihiro Oka, Haruo Sugiyama
  • Organizer: The 8th internatinal conference on WT1 in human neoplasia
  • Place of Presentation: KBS Kyoto Hall, Kyoto, Japan
  • Year and Date: 2015-11-19
  • Int'l Joint Research
• [Presentation] 急性骨髄性白血病に対するWT1ワクチン療法 (2015)
  • Author(s): 中田潤、中江吉希 、川上学 、森本創世子 、藤木文博 、中島博子 、西田純幸、保仙直毅、坪井昭博、尾路祐介、岡芳弘 、杉山治夫
  • Organizer: 第7回 血液免疫療法研究会
  • Place of Presentation: 東京大学 伊藤謝恩ホール
  • Year and Date: 2015-09-26