Development of exhaustion-resistant CAR-T cells for chronic infectious disease

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K19617
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Infectious disease medicine
• 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): 2016-04-01 – 2019-03-31
• Keywords: CAR-T細胞 / 疲弊 / 免疫チェックポイント / 共刺激シグナル / HVEM / HIV

Outline of Final Research Achievements

In this study, we have tried to develop HIV-specific CAR-T cells which are relatively resistant to exhaustion, and tested its usefulness as a model system. To achieve this goal, we have generated and analyzed HIV-specific CAR-T cells harboring different co-stimulatory signal domain (CSSD). Comparing to the CAR-T cells with a CD28- or 4-1-BB-derived CSSD, which are currently used for CAR-T cell development, we found that the CAR-T cells with a herpes virus entry mediator (HVEM)-derived CSSD exhibited enhanced effector functions and efficient and balanced differentiation to both central and effector memory subsets, associated with an elevated energy metabolism and a reduced level of exhaustion. Thus, the HVEM-derived CSSD may be useful for developing effective CAR-T cells.

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、HIV感染症を代表とする慢性感染症に応用するための基盤となる成果である。また、HVEM由来CSSDを用いることで疲弊抵抗的なCAR-T細胞を創出できる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の改善に役立てられると考えられる。