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

2021 Fiscal Year Final Research Report

• 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
• Keywords: CAR-T細胞 / 疲弊 / 免疫チェックポイント / 共刺激シグナル

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.

Free Research Field

免疫療法

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。