Off-the-shelf immunotherapy with CAR-gamma delta T cells

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K07674
• 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: Mie University
• Principal Investigator: Kato Takuma 三重大学, 医学系研究科, 准教授 (60224515)
• Co-Investigator(Kenkyū-buntansha): 王 立楠 三重大学, 医学系研究科, 助教 (00589484)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: キメラ抗原受容体 / γδＴ細胞 / off-the-shelf / アロ反応性 / 移植片対宿主反応 / 抗酸化因子 / 疲弊抵抗性

Outline of Final Research Achievements

Gamma/delta T cells were successfully transduced with a CAR specific to CEA with signaling domains of CD3zeta and CD28 (CEA.CAR-gd T cells). In a xenograft mouse model, CEA.CAR-gdT cells suppressed CEA+ tumor growth though a limited time window. Provision of GITR co-stimulation enhanced anti-tumor function of CEA.CAR-gd T cells, the result of which imposes additional measurers to be adopted in CAR-γδ T cells for an allogeneic adoptive immunotherapy. Therefore, CEA.CAR-gd T cells were prepared in the presence of NAC. NAC-pretreated CAR-T cells produced more IFN-g, enhanced serial killing function. These results suggest that supplementation of NAC during CAR-gd T cell preparation may be one of ways to obtain exhaustion resistant CAR-gdT cells which may have higher in vivo tumor control ability.

Free Research Field

免疫学

Academic Significance and Societal Importance of the Research Achievements

従来のCAR-Tでは、患者自身の末梢血からCAR-Tを調整するため、CAR-Tの質・量・均一性が安定せず、治療効果に大きな影響を及ぼす。さらに、病勢の進行した患者も含め、より多くの患者に対応するためには、調整時間を短くコストを下げなければならない。そこでアロ反応性を持たないγδ型T細胞を用いてCAR-Tを作製しoff-the-shelf化によるCAR-T輸注療法の適応拡大を目指した。その結果、CAR導入γδ型T細胞はCAR-T輸注療法の生物製剤としての有効性を示した。