Generation and analysis of exhausted CAR-T cell : For developing un-exhausted CAR-T cell

• Project/Area Number: 18K07272
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 50020:Tumor diagnostics and therapeutics-related
• Research Institution: Dokkyo Medical University
• Principal Investigator: Nunoya Jun-ichi 獨協医科大学, 医学部, 助教 (40466842)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: CAR-T細胞 / 疲弊 / 免疫チェックポイント / 共刺激シグナル / 転写因子 / HIV / 免疫療法

Outline of Final Research Achievements

In this study, we found that CAR-T cell with a CD28-derived co-stimulatory signal domain (CSSD) exhibited exhausted phenotype whereas the one with a herpes virus entry mediator-derived CSSD exhibited exhaustion-resistant phenotype. We also found that early exhaustion status of the CAR-T cell could affect responsiveness of the CAR-T cells. Phenotypic analysis of the CAR-T cells also showed that early CAR-T cell exhaustion is associated with CAR-mediated tonic signaling due to CAR clustering. In addition, we explored the factors for avoiding CAR-T cell exhaustion using CD28-CAR-T cell as a model system of exhausted CAR-T cell.

Academic Significance and Societal Importance of the Research Achievements

本研究の成果は、進行期造血器腫瘍で高い奏効率を示しているCAR-T細胞療法を、固形腫瘍に応用するための基盤となる成果である。疲弊CAR-T細胞の性状解析と疲弊CAR-T細胞を用いたスクリーニングから、CAR-T細胞の疲弊回避の可能性が示唆された。これは、固形腫瘍で見られるCAR-T細胞の疲弊化による不応答性を改善に役立てられると考えられる。

Research Products

• [Journal Article] Arrangement of VL and VH domains in VRC01-Based chimeric antigen receptor (CAR) affects functions and exhaustion status of CAR-T cells (2021)
  • Author(s): Nunoya Jun-ichi, Teramura Eijiro, Masuda Michiaki, Su Lishan
  • Journal Title: Re:GEN Open Volume: 1 Issue: 1 Pages: 26-39
  • DOI: 10.1089/regen.2021.0005
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Chimeric Antigen Receptor T Cell Bearing Herpes Virus Entry Mediator Co-stimulatory Signal Domain Exhibits High Functional Potency (2019)
  • Author(s): Nunoya Jun-ichi、Masuda Michiaki、Ye Chaobaihui、Su Lishan
  • Journal Title: Molecular Therapy - Oncolytics Volume: 14 Pages: 27-37
  • DOI: 10.1016/j.omto.2019.03.002
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Herpes virus entry mediator由来共刺激シグナル配列を有するキメラ抗原受容体発現T細胞(CAR-T細胞)は疲弊抵抗的な性状を示す (2022)
  • Author(s): 布矢純一, 伊牟田凪砂, 増田道明, Lishan Su
  • Organizer: 日本免疫治療学会
• [Presentation] キメラ抗原受容体(CAR)におけるVLおよびVH領域の配置はCAR-T細胞の機能だけでなく疲弊状態に影響を及ぼす (2021)
  • Author(s): 布矢純一, 寺村英次郎, 増田道明, Lishan Su
  • Organizer: 日本免疫治療学会
• [Presentation] Arrangement of the VH and VL domains in Chimeric Antigen Receptor (CAR) affects the effector functions of HIV-targeted CAR-T cells (2019)
  • Author(s): Jun-ichi Nunoya, Eijiro Teramura, Michiaki Masuda
  • Organizer: The Japanese Society for Virology
• [Presentation] Functional analysis and characterization of HIV-specific Chimeric Antigen Receptor (CAR)-T cells (2018)
  • Author(s): Jun-ichi Nunoya, Lishan Su, Michiaki Masuda
  • Organizer: The Japanese Society for Virology