Novel combination immunotherapy for glioma with new Tryptophan metabolizing enzyme inhibitor and Interferon

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K09322
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 56010:Neurosurgery-related
• Research Institution: University of Yamanashi
• Principal Investigator: Kawataki Tomoyuki 山梨大学, 大学院総合研究部, 医学研究員 (20303406)
• Co-Investigator(Kenkyū-buntansha): 松野 研司 安田女子大学, 薬学部, 教授 (50433214)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: IDO / malignant glioma / imunosupression / IFN-γ / a mouse model / glioblastoma

Outline of Final Research Achievements

Indoleamine 2,3-dioxygenase 1 (IDO1), catalyzes tryptophan (Trp) into kynurenine (Kyn) and is involved in immunotolerance during cancer progression. Previously, we have demonstrated strong expression of IDO1 and its correlation with prognosis in the pathological tissues of glioblastoma patients. Although many clinical trials are currently ongoing, investigating the efficacy of treatment with IDO1 inhibitors on cancer progression, the use of an IDO inhibitor alone has not been shown to be sufficient to decrease tumor progression thus far. We have produced three new IDO1 inhibitors and hypothesized that local IFN-γ inhibition induces IDO1 suppression, resulting in a synergistic anti-tumor effect in combination with IDO1 inhibitors. Oral administration of novel IDO1 inhibitors suppressed glioma tumor growth. Local administration of anti-IFN-γ antibodies had a synergistic effect on IDO1 inhibition.

Free Research Field

Brain tumor

Academic Significance and Societal Importance of the Research Achievements

トリプトファン代謝酵素Indoleamine 2,3 - dioxygenase (IDO)は、各種の癌細胞に認められ、免疫寛容に関与していることが推定されている。これまでに癌に対するIDO阻害剤の開発が行われているが、有用な創薬は見つかっていない。一方、IFN-gammaは、一般的には免疫賦活に働くが、近年、IDOならびにPDL1の賦活に働き免疫抑制的な機能の重要性が注目されている。我々は、IDO阻害薬を有効に働かせるためには、IFN-gammaの抑制が重要であるという仮説にも基づきこれを、マウスグリオーマモデルで示したことは意義深く、今後の癌治療への応用が期待できる成果である。