Utilizing ageing-related clonal haematopoesisfor effective CAR-T cell therapy

2023 Fiscal Year Final Research Report

• Project/Area Number: 22K19474
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 50:Oncology and related fields
• Research Institution: Keio University (2023); Aichi Cancer Center Research Institute (2022)
• Principal Investigator: Inoue Satoshi 慶應義塾大学, 医学部(信濃町), 講師 (30801930)
• Project Period (FY): 2022-06-30 – 2024-03-31
• Keywords: CAR-T細胞 / 加齢 / ゲノム異常

Outline of Final Research Achievements

We identified TET2, DNMT3A, and DUSP11 as aging-associated genetic mutations. First, we performed genetical ablabations of TET2, DNMT3A, and DUSP11 genes using the CRISPR Cas9 approach and analyzed the effects on the function of T cells and CAR-T cells. T cells or CAR-T cells with knockout of TET2 or DNMT3A genes indeed exhibited significant promotion of undifferentiated state (persistence),in agreement with previous reports. However, T cells and CAR-T cells with DUSP11 gene knockout did not show promotion of undifferentiated state (long-term survival capacity) as observed with TET2 or DNMT3A knockout T cells. Furthermore, no effects were observed on cell proliferation, cytokine and cytotoxic factor production, or cytotoxicity (anti-tumor effect). So far, we were unable to identify aging-related mutations that would favorably impact CAR-T cell immunotherapy.

Free Research Field

がん免疫

Academic Significance and Societal Importance of the Research Achievements

近年の正常部ゲノム解析により、多くの正常組織において、加齢によって体細胞変異が蓄積した細胞の一部が分化能を喪失したクローン性増殖能を獲得し、最終的に悪性化腫瘍を発症することが明らかになったが、これらは加齢によって発生する「前がん病変」を捉えることを目的とした研究であり、治療法に活用させることを意図した研究は皆無である。
本研究は、加齢に伴いT細胞で蓄積する、腫瘍化につながり得る遺伝子変異を逆にCAR-T細胞療法の治療効果改善に活用することを目指す、という新しい着想に基づく研究計画であり、既存の治療戦略の延長線にのらない治療法である。