Development of combinatorial CAR-T cell therapy improving immunosupressive tumor microenvironment

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K07641
• 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: Kyoto Prefectural University of Medicine
• Principal Investigator: Yagyu Shigeki 京都府立医科大学, 医学(系)研究科(研究院), 助教 (10572547)
• Co-Investigator(Kenkyū-buntansha): 吉田 秀樹 京都府立医科大学, 医学(系)研究科(研究院), 助教 (10643546) ; 菊地 顕 京都府立医科大学, 医学(系)研究科(研究院), 特任講師 (40453104)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: CAR-T細胞 / 固形腫瘍 / 免疫疲弊 / 神経芽腫

Outline of Final Research Achievements

To enhance the efficacy of CAR-T cell therapy for solid tumors, it is important to suppress immunosuppressive mechanisms by the tumor microenvironment. In this study, we investigated the potential of molecularly targeted drugs and combination therapies to prevent CAR-T cells from being exhausted by the immunosuppressive tumor microenvironment and to improve the efficacy of CAR-T cell therapy. A synergistic antitumor effect was observed in the trametinib plus GD2-CAR-T cell combination therapy group compared to the GD2-CAR-T cell monotherapy group in neuroblastoma-bearing murine xenograft model, regardless of the mutation status of Raf/MEK pathway. These results suggest that trametinib suppresses excessive activation and exhaustion of CAR-T cells and synergistically enhances antitumor effects of GD2-CAR-T cells. Based on these findings, the efficacy of alectinib, an ALK inhibitor, in combination with GD2-CAR-T cells in ALK-mutant neuroblastoma is also being investigated.

Free Research Field

遺伝子細胞療法

Academic Significance and Societal Importance of the Research Achievements

固形腫瘍に対するCAR-T細胞療法の応用が期待されているが、CAR-T細胞療法の効果を向上させるためには、さらなる遺伝子改変や併用療法の開発が望まれている。本研究は、すでに他疾患で承認されているRaf/MEK阻害剤が、CAR-T細胞の過剰活性化と疲弊を抑制することで相乗的な効果を発揮することを明らかにした。今後、神経芽腫に対してGD2-CAR-T細胞療法が臨床応用されていく中で、分子標的薬との併用療法が有望であることが証明された点で学術的、社会的意義が高いと考えられる。