Development of immunotherapy against malignancies relapsed post-transplant using TCR-T cells specific for mismatched HLAs

• Project/Area Number: 18K08341
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: Nagoya University
• Principal Investigator: AKATSUKA YOSHIKI 名古屋大学, 医学系研究科, 特任教授 (70333391)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2020: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2019: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: HLA-DP / アロ抗原 / 同種造血幹細胞移植 / 移植後再発白血病 / 養子細胞免疫療法 / 同種造血細胞移植 / 再発 / 遺伝子改変T細胞 / アロ免疫 / 遺伝子改変T細胞療法 / 養子免疫療法 / 造血器悪性腫瘍 / 同種移植

Outline of Final Research Achievements

We attempted to generate T cell clones specific for mismatched HLA-DP molecules from peripheral blood T cells of healthy volunteers and patients who underwent HLA-DP-mismatched allogeneic hematopoietic cell transplantation from their unrelated donor. Several clones specific for HLA-DPB1*09:01and DPB1*02:01 were isolated from the volunteers' blood and those specific for DPB1*09:01 were isolated from the patients. The former clones showed weak reactivity against DPB1*09:01-positive primary leukemic blasts from various patients while the latter clones showed significant IFN-γ production and cytotoxicity toward the same targets. Healthy T cells that were gene-modified with a retrovirus encoding T cell receptor cDNA of the DPB1*09:01-specific T cell clone successfully demonstrated the identical specificity and cytokine production capacity against the cognate target cells.

Academic Significance and Societal Importance of the Research Achievements

本研究を通じて樹立されたT細胞クローンが認識するHLA-DPB1*09:01およびDPB1*02:01は日本人間の同種造血細胞移植で不適合が起こりやすいHLA-DP型を認識するものであった。難治性白血病患者がこれらのHLA-DP座が不適合のドナーより移植を受けた後に再発してしまった場合、今回樹立したクローンやそのT細胞受容体遺伝子を導入されたT細胞を患者に投与することで、再発した白血病に対して抗原特異的な養子免疫細胞療法となると期待される。今後さらに日本人に多い3種類程度のHLA-DP型に特異的なT細胞クローンを樹立することで、約7割程度の患者に免疫療法をすることが可能となると考えられる。

Research Products

• [Journal Article] 不適合アロ抗原認識抗体を用いた移植後再発白血病に対するCAR-T細胞の開発 (2021)
  • Author(s): 赤塚美樹
  • Journal Title: Bio Clinica Volume: 36 Pages: 56-63
• [Journal Article] がん免疫療法の展開と展望 (2020)
  • Author(s): 赤塚美樹
  • Journal Title: 現代医学 Volume: 67 Pages: 37-46
  • Open Access
• [Journal Article] TCR-Like CAR-T Cells Targeting MHC-Bound Minor Histocompatibility Antigens. (2020)
  • Author(s): Akatsuka Y
  • Journal Title: Front Immunol Volume: 11 Pages: 257-257
  • DOI: 10.3389/fimmu.2020.00257
  • Peer Reviewed / Open Access
• [Journal Article] Progress in immune checkpoint inhibitor therapies (2019)
  • Author(s): Akatsuka Y
  • Journal Title: Rinsho Ketsueki Volume: 60 Pages: 1341-1350
  • NAID: 130007724660
• [Journal Article] Improving TCR affinity on 293T cells (2019)
  • Author(s): Ohta Rieko、Demachi-Okamura Ayako、Akatsuka Yoshiki、Fujiwara Hiroshi、Kuzushima Kiyotaka
  • Journal Title: Journal of Immunological Methods Volume: 466 Pages: 1-8
  • DOI: 10.1016/j.jim.2018.11.010
  • Peer Reviewed / Open Access
• [Journal Article] Antitumor activity of CAR-T cells targeting the intracellular oncoprotein WT1 can be enhanced by vaccination. (2018)
  • Author(s): Akahori Y, Wang L, Yoneyama M, Seo N, Okumura S, Miyahara Y, Amaishi Y, Okamoto S, Mineno J, Ikeda H, Maki T, Fujiwara H, Akatsuka Y, Kato T, Shiku H.
  • Journal Title: Blood. 2018 Sep 13;132(11): Volume: 132 Issue: 11 Pages: 1134-1145
  • DOI: 10.1182/blood-2017-08-802926
  • Peer Reviewed / Open Access
• [Presentation] 同種造血細胞移植後の再発白血病に対する新規アロ養子免疫療法の開発 (2020)
  • Author(s): 赤塚美樹
  • Organizer: 第41回日本炎症・再生医療学会
  • Invited
• [Presentation] 不適合HLA-DP抗原を標的とする同種造血細胞移植後の養子免疫療法の開発 (2020)
  • Author(s): 赤塚美樹、楫屋良子、西尾信博、一戸辰夫、岡村文子、西川博嘉
  • Organizer: 第24回日本がん免疫学会総会
• [Presentation] 不適合HLA-DPB1*02:01抗原を標的とした同種移植後細胞免疫療法の開発 (2020)
  • Author(s): 赤塚美樹, 勝山直哉, 川瀬孝和、西尾信博, 楫屋良子, 岡村文子, 一戸辰夫
  • Organizer: 第12回日本血液疾患免疫療法学会
• [Presentation] Cellular therapies against recurring hematological malignancies after allogeneic HCT (2020)
  • Author(s): Yoshiki Akatska
  • Organizer: The 25th meeting of Asia Pacific Blood and Marrow Transplantation Group
  • Invited
• [Presentation] 不適合HLA-DP抗原を標的とする同種移植後細胞免疫療法の検討 (2020)
  • Author(s): 勝山 直哉, 楫屋 良子, 白石 圭子, 西尾 信博, 一戸 辰夫, 赤塚 美樹
  • Organizer: 第42回日本造血細胞移植学会総会
• [Presentation] 不適合HLA-DP抗原を標的とした同種移植後細胞免疫療法の検討 (2019)
  • Author(s): 赤塚美樹, 勝山直哉, 白石圭子, 楫屋良子, 岡文子
  • Organizer: 第11回血液疾患免疫療法学会学術集会
• [Patent(Industrial Property Rights)] Ｔ細胞受容体 (2021)
  • Inventor(s): 赤塚美樹、他2名
  • Industrial Property Rights Holder: 名古屋大学
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2021-055988
  • Filing Date: 2021