Development of CAR function-tuning technology that contributes to the optimization of CAR-T cell therapy

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K20462
• Project/Area Number (Other): 19H05552 (2019)
• Research Category: Grant-in-Aid for Challenging Research (Pioneering)
• Allocation Type: Multi-year Fund (2020); Single-year Grants (2019)
• Review Section: Medium-sized Section 47:Pharmaceutical sciences and related fields
• Research Institution: Osaka University
• Principal Investigator: Okada Naoki 大阪大学, 大学院薬学研究科, 教授 (90312123)
• Project Period (FY): 2019-06-28 – 2023-03-31
• Keywords: キメラ抗原受容体 / 構造活性相関 / 細胞療法 / 腫瘍免疫

Outline of Final Research Achievements

(1) Among CARs constructed using various scFv clones, there are structures that are expressed on the T cell membrane but have very poor antigen-binding affinity, or that aggregate in cytosol.
(2) The hinge domain (HD) defines the expression efficiency and signal input threshold of CAR by its structure (length and flexibility) or complex formation, and the transmembrane domain (TMD) defines CAR expression stability on the cell membrane or subcellular localization of CAR.
(3) When designing the intracellular signal transduction domain (STD) of the second-generation CAR, it is necessary to consider not only the signal characteristics of STDs, but also CAR intracellular structural changes.

Free Research Field

細胞療法学・ワクチン学

Academic Significance and Societal Importance of the Research Achievements

がん免疫療法が標的とする抗原分子の多くは、量の多寡はあるもののがん細胞のみならず正常細胞にも発現している。抗体療法やワクチン療法といった患者体内の免疫細胞にがん細胞の排除を担わせる免疫療法においては、標的分子のがん細胞/正常細胞発現比の大きいことが主作用と副作用の分離に必須の条件とされてきた。一方、それ自身ががん細胞を傷害するCAR-T細胞医薬においては、CAR機能のチューニングを行うことによって標的分子密度をより厳密に見分けた作用発揮のON/OFFが実現できるかもしれない。本研究の成果たるCARの構造活性相関情報は、有効性増強や副作用低減のための構造情報を導入したCAR設計に貢献する。