Augmentation and mechanism of CAR-T cell therapy by naive CD4+ T cell help

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K09195
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 55020:Digestive surgery-related
• Research Institution: Mie University
• Principal Investigator: WANG LINAN 三重大学, 医学系研究科, 産学官連携講座助教 (00589484)
• Co-Investigator(Kenkyū-buntansha): 加藤 琢磨 三重大学, 医学系研究科, 准教授 (60224515)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: CAR-T細胞療法 / 固形がん / primaryCD4+T細胞

Outline of Final Research Achievements

Recent clinical trials of adoptive therapy with CAR-T cells targeting CD19 have shown an impressive efficacy in patients with hematologic malignancies and were for the use by the US FDA. However, wider application of this approach for the treatment of solid tumors has faced a number of challenges including poor expansion and persistence in vivo, insufficient trafficking to tumors, and impaired function due to immunosuppressive mechanisms operating in tumor microenvironment. CD4+ T cells have been shown to play a critical role in orchestrating antitumor immune responses directly and indirectly facilitating CTL activities. However, utilization of CD4+T cells in CAR-T cell therapy has rarely practiced and yet not fully appreciated. In the present study, we addressed whether co-transfer of CD4+ T cells might improve effectiveness of CAR-T cell therapy.

Free Research Field

遺伝子免疫細胞治療学

Academic Significance and Societal Importance of the Research Achievements

申請者らは、CD3zに加えてCD28あるいはGITR由来のシグナル伝達ドメインを搭載したCEA特異的28z型CARとzG型CAR-Tを作製し、CEA陽性腫瘍担癌7日目にリンパ球減少性の前処置を施したマウスに輸注する治療モデル系において、未加工のCD4T（primary CD4T）の同時輸注にて、CD4Tは自己抗原ペプチドと結合したMHCClassIIにより増殖・ 活性化しIFN-gやIL-2などのサイトカインを産生することにより特異性を付与しなくとも輸注CD4Tの活性化とヘルパー機能が誘導された。抗腫瘍効果が顕著に増強されることを認められた。