Development of Novel Vaccine Immunotherapy for Malignant Glioma

2019 Fiscal Year Final Research Report

• Project/Area Number: 17H04306
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Neurosurgery
• Research Institution: Keio University
• Principal Investigator: Toda Masahiro 慶應義塾大学, 医学部(信濃町), 准教授 (20217508)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: 悪性神経膠腫 / 免疫チェックポイント / PD-1 / VEGFR / ネオアンチゲン

Outline of Final Research Achievements

In the present study, we established a novel combinational immunotherapy using epitope peptide targeting glioma neoantigen and vascular endothelial growth factor receptor (VEGFR)1/2, and anti-programmed cell death (PD)-1. Induced cytotoxic T lymphocytes could kill not only tumor vessel cells but also tumor cells and immunosuppressive regulatory T cells (Tregs) expressing VEGFRs. Remarkable prolonged survival was achieved in the glioma mouse model. Furthermore, we revealed that VEGFR2 is highly expressed in the glioma stem cells (GSCs). This approach could inhibit the proliferation of GSCs in an orthotopic mouse model. The histopathological findings of pre- and post-VEGFRs vaccination glioblastoma specimens demonstrated that more apoptosis was detected in tumor cells, and the number of Foxp3-positive cells decreased after vaccination.
This novel immunotherapy targeting a large variety of cells has the possibility to show higher treatment efficacy for the patients with malignant glioma.

Free Research Field

脳神経外科学

Academic Significance and Societal Importance of the Research Achievements

グリオーマ細胞におけるNeoantigenを標的とするエピトープペプチドと抗PD-1抗体を組み合わせた複合免疫療法に、さらにVEGFR1/VEGFR2を標的とするエピトープペプチドを上乗せすることで、腫瘍細胞のみならず、腫瘍血管内皮細胞や免疫抑制性の制御性T細胞といった腫瘍関連微小環境をも統合的に標的可能であった。さらにBTSCには特にVEGFR2が高発現するため、BTSCを標的とする治療にも応用可能であった。腫瘍の増大には、腫瘍細胞のみならず周囲微小環境が重要な役割を果たすため、本複合免疫療法は新たな治療戦略となり得る。