2023 Fiscal Year Final Research Report

The investigation of factors influencing on therapeutic effect of anti-PD-1 antibody therapy for hepatocellular carcinoma by comprehensive analysis of intestinal flora

Research Project

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Project/Area Number	19K07788
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	Kurume University
Principal Investigator	Torimura Takuji 久留米大学, 付置研究所, 客員教授 (60197986)
Co-Investigator(Kenkyū-buntansha)	光山慶一久留米大学, 医学部, 教授 (20200066) 岩本英希久留米大学, 医学部, 助教 (40529541) 古賀浩徳久留米大学, 医学部, 教授 (90268855)
Project Period (FY)	2019-04-01 – 2024-03-31
Keywords	肝細胞癌 / 腸内細菌叢 / 免疫チェックポイント阻害剤 / 抗腫瘍効果 / 血管新生抑制 / シンバイオティックス
Outline of Final Research Achievements	In mouse tumor model, anti-PD-L1 antibody and anti-VEGF antibody treatment significantly suppressed tumor growth. In symbiotics administrated group, anti-PD-L1 antibody and anti-VEGF antibody treatment also suppressed tumor growth. Administration of symbiotics changed the composition of bacterial flora in mouse colon. In clinical trial, median survival time of all 34 patients with hepatocellular carcinoma treated with Atezolizumab (anti-PD-L1 antibody) and bevacizumab (anti-VEGF antibody) was 13.7 months. There was no significant difference in diversity of bacterial flora between responder group(CR+PR) and non-renponder group(SD+PD). In responder group, Acidominococcaceae and Monoglobaceae were significantly increased. On the other hand, Erysipelatoclostridiae was significantly increased in non-responder group. Overall survival and progression free survival were significantly prolonged in HCC patients with Akkermansiaceae-rich bacterial flora.
Free Research Field	肝臓病学
Academic Significance and Societal Importance of the Research Achievements	今回マウス肝癌モデルを用いた検討では、シンバイオティックスを投与すると腸内細菌叢が変化し、抗PD-L1抗体+抗VEGF抗体の抗腫瘍効果が有意差はないものの増強した。臨床研究においては、抗PD-L1抗体+抗VEGF抗体を用いた治療を行った症例において、Akkermansiaceaeが多い症例では有意に無増悪生存期間と全生存期間が延長していた。以上の結果から、進行肝細胞癌において、将来的に腸内細菌叢を変化させることで免疫チェックポイント阻害剤を用いた治療効果を増強できる可能性が示唆された。本研究は、進行肝細胞癌の予後改善に繋がる意義のある研究であると考えられる。