Exploring biomarkers concerning NK immunity that favor treatment discontinuation in CML patients

• Project/Area Number: 17K09908
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: Saga University
• Principal Investigator: Kimura Shinya 佐賀大学, 医学部, 教授 (80359794)
• Co-Investigator(Kenkyū-buntansha): 安藤 寿彦 佐賀大学, 医学部, 准教授 (30363097) ; 久保田 寧 佐賀大学, 医学部, 講師 (60570413)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2017: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
• Keywords: 慢性骨髄性白血病 / チロシンキナーゼ阻害剤 / 免疫 / NK 免疫 / NK 細胞 / バイオマーカー

Outline of Final Research Achievements

We reported that patients with chronic myeloid leukemia (CML) who had polymorphisms such as KIR3DL1*005 on NK cells had significantly better response to tyrosine kinase inhibitors (TKIs) (Cancer Immunol Res 2018).
Based on the difference in the results of second-line dasatinib discontinuation study (Lancet Haematol 2015) and first-line dasatinib discontinuation study (Lancet Haematol 2020) both which we performed, we confirmed that the sustained molecular response after dasatinib discontinuation depended not on NK immunity but on T cell immunity (in submission).

Academic Significance and Societal Importance of the Research Achievements

TKIs によってCMLの予後は格段に改善し、ほぼ健常人と同等の生命予後となった。しかし長期的な TKIs 服用による有害事象や高額な費用が問題となってきた。我々は、1次使用でも2次使用でも半数近い患者がダサチニブが中止できること、そして免疫細胞は効果発現と中止後の維持では、NK細胞とT細胞などの免疫細胞が役割分担しながら働いていることを明らかにした。
これらの結果は、CML患者の予後をさらに改善するでなく、個人の経済的負担そして国全体の医療費の削減にも貢献できる成果である。

Research Products

• [Int'l Joint Research] University of Toronto(カナダ)
• [Int'l Joint Research] Sungkyunkwan University/Samsung Medical Center/Chonnam National University(韓国)
• [Journal Article] Phosphorylated ERK1/2 in CD4 T cells is associated with acute GVHD in allogeneic hematopoietic stem cell transplantation (2020)
  • Author(s): Itamura H, Shindo T, Yoshida S, Ishikawa T, Kimura S
  • Journal Title: Blood Avvances Volume: 4 Issue: 4 Pages: 667-671
  • DOI: 10.1182/bloodadvances.2019000343
  • NAID: 120006878504
  • Peer Reviewed / Open Access
• [Journal Article] Treatment-free remission after first-line dasatinib discontinuation in patients with chronic myeloid leukaemia (first-line DADI trial): a single-arm, multicentre, phase 2 trial (2020)
  • Author(s): Kimura Shinya、Imagawa Jun、Murai Kazunori、Hino Masayuki、Kitawaki Toshio、Okada Masaya、Tanaka Hideo、Shindo Motohiro、Kumagai Takashi、Ikezoe Takayuki、Uoshima Nobuhiko、Sato Tsutomu、Watanabe Reiko、Kowata Shugo、Hayakawa Masaya、Hosoki Takaaki、Ikeda Kazuhiko、et al.
  • Journal Title: The Lancet Haematology Volume: 7 Issue: 3 Pages: 218-225
  • DOI: 10.1016/s2352-3026(19)30235-2
  • Peer Reviewed / Open Access
• [Journal Article] Naked antisense double-stranded DNA oligonucleotide efficiently suppresses BCR-ABL positive leukemic cells. (2019)
  • Author(s): Hoshiko T, Kubota Y, Akisawa T, Watanabe T, Tanigawara K, Yano J, Kimura S.
  • Journal Title: Invest New Drugs Volume: － Issue: 4 Pages: 1012-1019
  • DOI: 10.1007/s10637-019-00862-9
  • Peer Reviewed / Open Access
• [Journal Article] A new highly sensitive real-time quantitative-PCR method for detection of BCR-ABL1 to monitor minimal residual disease in chronic myeloid leukemia after discontinuation of imatinib (2019)
  • Author(s): 26.Kitamura H, Tabe Y, Ai T, Tsuchiya K, Yuri M, Misawa S, Horii T, Kawaguchi A, Ohsaka A, Kimura S
  • Journal Title: PLoS One Volume: 14 Issue: 3 Pages: e0207170-e0207170
  • DOI: 10.1371/journal.pone.0207170
  • Peer Reviewed / Open Access
• [Journal Article] C/EBPβ is a critical mediator of IFNα-induced exhaustion of chronic myeloid leukemia stem cells. (2019)
  • Author(s): Yokota A, Hirai H, Sato R, Adachi H, Sato F, Hayashi Y, Sato A, Kamino N, Miura Y, Nakano M, Tenen DG, Kimura S, Tashiro K, Maekawa T
  • Journal Title: Blood Advances Volume: 3 Issue: 3 Pages: 476-488
  • DOI: 10.1182/bloodadvances.2018020503
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] HMGCLL1 is a predictive biomarker for deep molecular response to imatinib therapy in chronic myeloid leukemia. (2018)
  • Author(s): Park J.-H., Woo Y.-M., Youm E., Hamad N., Won H.-H., Naka K., Park E.-J., Park J.-H., Kim H.J., Kim S.-H., Kim H., Ahn J.-S., Sohn S.-K., Moon J.-H., Jung C.-W., Park S., Lipton J., Kimura S., Jong-Won Kim J.-W., Kim D.
  • Journal Title: Leukemia Volume: epub ahead of print Issue: 6 Pages: 1439-1450
  • DOI: 10.1038/s41375-018-0321-8
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Allelic polymorphisms of KIRs and HLAs predict favorable responses to tyrosine kinase inhibitors in CML. (2018)
  • Author(s): Ureshino H, Shindo T, Kojma H, Kusunoki Y, Miyazaki Y, Tanaka H, Saji H, Kawaguchi A, Kimura S
  • Journal Title: Cancer Immunology Research Volume: 6 Pages: 745-754
  • Peer Reviewed
• [Journal Article] Feasibility of the Imatinib Stop Study in the Japanese Clinical Setting: Delightedly Overcome CML Expert Stop TKI Trial (DOMEST Trial). (2018)
  • Author(s): Fujisawa S, Ueda Y, Usuki K, Kobayashi K, Kondo E, Doki N, Nakao T, Kanda Y, Kosugi N, Kosug H, Kumagai T, Harada H, Shikami M, Maeda Y, Sakura T, Inokuchi K, Saito A, Nawa Y, Ogasawara M, Nishida J, Kondo T, Yoshida C, Kuroda H, Tabe Y, Maeda Y, Imajo K, Kojima K, Morita S, Komukai S, Kawaguchi A, Sakamoto J, Kimura S
  • Journal Title: International Journal of Clinical Oncology Volume: 24 Issue: 4 Pages: 445-453
  • DOI: 10.1007/s10147-018-1368-2
  • Peer Reviewed
• [Journal Article] Final 3-year Results of the Dasatinib Discontinuation Trial in Patients With Chronic Myeloid Leukemia Who Received Dasatinib as a Second-line Treatment (2018)
  • Author(s): Okada M, Imagawa J, et al.
  • Journal Title: Clin Lymphoma Myeloma Leuk. Volume: 18 Issue: 5 Pages: 353-360
  • DOI: 10.1016/j.clml.2018.03.004
  • NAID: 120006463738
  • Peer Reviewed / Open Access
• [Journal Article] Anxiety and depression associated with tyrosine kinase inhibitor discontinuation in patients with chronic myeloid leukemia. (2018)
  • Author(s): Sogawa R, Kimura S, Yakabe R, Mizokami Y, Tasaki M, Sueoka-Aragane N, Narisawa Y, Kimura S
  • Journal Title: International Journal of Clinical Oncology Volume: 23 Issue: 5 Pages: 974-979
  • DOI: 10.1007/s10147-018-1275-6
  • Peer Reviewed
• [Presentation] Achievements and limitations of tyrosine kinase inhibitors, and development of demethylating agents (2019)
  • Author(s): Shinya Kimura
  • Organizer: The 16th Nikko International Symposium
  • Int'l Joint Research / Invited
• [Presentation] ニロチニブのデータを用いた慢性骨髄性白血病治療における長期無治療寛解による財政影響分析 (2019)
  • Author(s): 木村晋也
  • Organizer: 日本血液学会総会
• [Presentation] Imatinib STop Study Feasible to Japanese Clinical Setting (2018)
  • Author(s): Usuki K, Ueda T, Kimura S et al.
  • Organizer: European Hematology Association
  • Int'l Joint Research / Invited
• [Presentation] Targeting BCR-ABL by DNA/RNA heteroduplex oligonucleotide (2018)
  • Author(s): Kimura S, Hosiko T, Yano J, et al.
  • Organizer: John Goldman CML conference
  • Int'l Joint Research / Invited
• [Presentation] Allelic polymorphisms of KIR and HLA predict favorable responses to tyrosine kinase inhibitor in chronic myeloid leukemia (2017)
  • Author(s): Shinya Kimura
  • Organizer: 19th John Goldman CML conference
  • Int'l Joint Research / Invited
• [Remarks] 佐賀大学医学部内科学講座 血液・呼吸器・腫瘍内科
  • URL: http://www.saga-hor.jp/main/
• [Patent(Industrial Property Rights)] 成人T細胞性白血病/リンパ腫の検出方法 (2019)
  • Inventor(s): 渡邊達郎、末岡榮三郎、木村晋也、嬉野博志
  • Industrial Property Rights Holder: 渡邊達郎、末岡榮三郎、木村晋也、嬉野博志
  • Industrial Property Rights Type: 特許
  • Filing Date: 2019
  • Overseas