Development of a combinatorial approach of antibody therapeutics and adoptive immunotherapy for cancer

2022 Fiscal Year Final Research Report

• Project/Area Number: 21K19422
• 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: Aichi Cancer Center Research Institute
• Principal Investigator: Kagoya Yuki 愛知県がんセンター(研究所), 腫瘍免疫応答研究分野, 客員研究員 (70706960)
• Project Period (FY): 2021-07-09 – 2023-03-31
• Keywords: キメラ抗原受容体 / 免疫細胞療法 / T細胞疲弊 / 抗体医薬 / 免疫チェックポイント阻害剤 / エピジェネティック因子 / メモリーT細胞

Outline of Final Research Achievements

In this study, we aimed to develop chimeric antigen receptor-engineered T cells that secrete antibody drugs such as immune checkpoint inhibitors to enhance its therapeutic efficacy. We designed the mAb drugs at genetic levels and examined their efficacy and safety when ectopically expressed in CAR-T cells. We optimized the mAb sequences based on the secretion efficiency as well as toxicity to the T cells. We confirmed that the mAb-engineered T cells can induce objective antitumor response in vitro. In addition to this, we also aimed to improve functions of antitumor T cells so that they can maintain efficient drug secretion. We identified that T cells can acquire long-lived potential by ablating specific epigenetic genes.

Free Research Field

免疫学

Academic Significance and Societal Importance of the Research Achievements

キメラ抗原受容体（CAR）導入T細胞療法は、一部の血液腫瘍に対して高い治療効果を示すものの、固形がんを中心とする他の多くのがんでは持続的な効果が得られていない。輸注されたT細胞が、持続的に抗原刺激を受けることに伴い徐々に細胞傷害活性を失う疲弊と、終末分化状態に陥り細胞分裂能を失うことが課題である。本研究成果はT細胞が疲弊状態に陥った際に、CARによる抗腫瘍効果とは独立した機序で治療効果を維持できるシステム、及びCAR-T細胞が体内で長期間生存するための遺伝子改変方法に関する研究開発であり、上記の問題解決に寄与することが期待される。