Development of preclinical models of donor-derived gene-modified lymphocyte infusion for tumor-relapse after allogeneic hematopoietic cell transplantation and evaluation of efficacy and safety

• Project/Area Number: 17K09949
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: Mie University
• Principal Investigator: TAWARA Isao 三重大学, 医学部附属病院, 講師 (80378380)
• Co-Investigator(Kenkyū-buntansha): 池田 裕明 長崎大学, 医歯薬学総合研究科(医学系), 教授 (40374673)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 造血細胞移植 / 移植後腫瘍再発 / ドナーリンパ球輸注 / 腫瘍特異的リンパ球 / 移植片対宿主病 / 造血幹細胞移植 / 移植片対腫瘍効果 / 遺伝子改変細胞 / 遺伝子改変リンパ球 / 腫瘍特異的遺伝子改変免疫細胞 / Ｔ細胞受容体遺伝子改変 / ＧＶＨＤ

Outline of Final Research Achievements

We generated murine models of tumor relapse after major histocompatibility complex (MHC)-matched or mismatched allogeneic hematopoietic cell transplantation (HCT) and performed tumor-specific donor lymphocyte infusion (DLI) 2 or 8 weeks after HCT. Anti-tumor effect was observed in each setting and GVHD was aggravated graft-vs-host disease (GVHD) in the animals when we performed tumor-specific DLI 2 weeks after HCT. GVHD aggravation was observed only in the recipients of MHC-matched HCT, not in those of MHC-mismatched HCT when we performed tumor-specific DLI 8 weeks after HCT. Our pre-clinical data suggest that GVHD aggravation caused by tumor-specific DLI is dependent on timing and MHC disparity. This study will contribute to clinical development of tumor-specific DLI for the tumor-relapsed patients after allogeneic HCT.

Academic Significance and Societal Importance of the Research Achievements

本研究は、同種造血細胞移植における臨床的課題である移植後腫瘍再発に対して、腫瘍特異的遺伝子改変ドナーリンパ球輸注療法（DLI）を実施することを念頭においた、前臨床研究である。研究成果は、腫瘍特異的DLIを実施する際に懸念されるGVHDへの影響が、レシピエントの状態、MHC適合度によって異なること示しており、より効果的で安全な腫瘍特異的DLIの臨床開発において、重要な基礎データになると考えられる。

Research Products

• [Journal Article] Safety and persistence of WT1-specific T-cell receptor gene-transduced lymphocytes in patients with AML and MDS. (2017)
  • Author(s): Tawara I, Kageyama S, Miyahara Y, Fujiwara H, Nishida T, Akatsuka Y, Ikeda H, Tanimoto K, Terakura S, Murata M, Inaguma Y, Masuya M, Inoue N, Kidokoro T, Okamoto S, Tomura D, Chono H, Nukaya I, Mineno J, Naoe T, Emi N, Yasukawa M, Katayama N, Shiku H.
  • Journal Title: Blood Volume: 130 Issue: 18 Pages: 1985-1994
  • DOI: 10.1182/blood-2017-06-791202
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 新しい腫瘍細胞株を用いたマウスMHC半合致骨髄移植後シクロフォスファミド投与モデル (2019)
  • Author(s): 俵功、伊野和子、藤枝敦史、坪井順哉、西村廣明、宮原慶裕、大石晃嗣、桝屋正浩、珠玖洋、片山直之
  • Organizer: 第41回日本造血細胞移植学会総会
• [Presentation] シクロフォスファミド抵抗性腫瘍細胞株を用いたマウスMHC半合致移植モデルの作製 (2019)
  • Author(s): 俵功、西村廣明、坪井順哉、伊野和子、景山裕紀、大石晃嗣、桝屋正浩、片山直之
  • Organizer: 第81回日本血液学会学術集会
• [Presentation] 新しい腫瘍細胞株を用いたマウスMHC半合致骨髄移植後シクロフォスファミド投与モデル (2019)
  • Author(s): 俵 功、伊野 和子、藤枝 敦史、坪井 順哉、西村 廣明、宮原 慶裕、大石 晃嗣、桝屋 正浩、珠玖 洋、片山 直之
  • Organizer: 第41回日本造血細胞移植学会総会
• [Presentation] WT1-specific TCR gene-transduced Lymphocytes (2018)
  • Author(s): Isao Tawara
  • Organizer: 2018 Korean Society of Experimental Hematology 5th Annual Meeting
  • Invited
• [Presentation] Tumor-specific TCR-engineered Donor Lymphocytes Infusion for Tumor Relapse after Hematopoietic Stem Cell Transplantation in Mice. (2017)
  • Author(s): Tawara Isao, Okamori Kana, Shiku Hiroshi, Ikeda Hiroaki, Katayama Naoyuki
  • Organizer: The 8th JSH Internationalsymposium
  • Int'l Joint Research
• [Presentation] Tumor-Specific Donor Lymphocyte Infusion after Allogeneic Hematopoietic Stem Cell Transplantation (2017)
  • Author(s): Tawara Isao, Katayama Naoyuki, Shiku Hiroshi, Ikeda Hiroaki
  • Organizer: 第76回日本癌学会学術総会
• [Presentation] Tumor-specific Donor Lymphocyte Infusion for Tumor Relapse after Hematopoietic Cell Transplantation. (2017)
  • Author(s): Tawara Isao, Okamori Kana, Shiku Hiroshi, Ikeda Hiroaki, Katayama Naoyuki
  • Organizer: 第79回日本血液学会学術集会