Development of CAR-T cells to treat recurring leukemia post-HCT by targeting mismatched HLA-DP

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K08369
• 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): 2021-04-01 – 2024-03-31
• Keywords: 移植片対白血病効果 / キメラ抗原受容体T細胞 / HLA-DP / アロ抗原

Outline of Final Research Achievements

In HLA-8/8-matched unrelated allogeneic transplantation for hematological malignancies, HLA-DP is often mismatched at a rate of 70%, which can be applied to treat or prevent post-transplant relapsed malignancy by graft-versus-tumor effect. We have established a technique to flow-sort hybridoma cells which produce antibodies of interest by introducing CD64 Fc receptor into the hybridoma cells in advance and allow the produced antibodies to bind to the self CD64. With this method, two hybridomas producing antibodies specific for HLA-DPB1*09:01 (common in Japanese) were isolated so far. In parallel, by using RT-PCR we cloned genes encoding IgG antibodies specific for several HLA subtypes and generated single-chain antibodies that retain the original antibodies’ specificity. Thus, we currently working on generation of chimeric antigen receptor-gene modified T cells specific for HLA-DP of interest.

Free Research Field

血液免疫学

Academic Significance and Societal Importance of the Research Achievements

同種造血細胞移植におけるドナー／患者間のHLA-DP不適合はGVT効果発現に重要である。不適合HLA-DPを認識するT細胞の樹立は容易ではなく、事前にHLA-DPを認識する抗体を樹立し、その遺伝子配列を元にキメラ抗原受容体T細胞調製に必要なベクターを作製しておけば直ちに養子免疫療法を実施することが可能となる。この抗HLA-DP抗体は殆ど報告がなく、我々はフローサイトメトリーを使った方法で狙った抗原に特異的な抗体を作るハイブリドーマ細胞を樹立する方法を確立した。この2つの技術を組み合わせることで将来的にさまざまなHLA-DP型不適合に対応するキメラ抗原受容体T細胞を提供できると考えられる。