Development of new immunotherapy for lung cancer by combined application of diabetes drug metformin and anti-PD-1 antibody

• Project/Area Number: 16K15637
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Respiratory surgery
• Research Institution: Okayama University
• Principal Investigator: Miyoshi Shinichiro 岡山大学, 医歯薬学総合研究科, 特命教授 (00190827)
• Co-Investigator(Kenkyū-buntansha): 豊岡 伸一 岡山大学, 医歯薬学総合研究科, 教授 (30397880) ; 山本 寛斉 岡山大学, 大学病院, 助教 (40467733) ; 阪口 政清 岡山大学, 医歯薬学総合研究科, 教授 (70379840) ; 宗 淳一 岡山大学, 大学病院, 講師 (90559890)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000); Fiscal Year 2018: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2017: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 肺癌 / メトホルミン / 抗PD-1抗体 / 癌 / 外科

Outline of Final Research Achievements

We performed the research to develop new immunotherapy for lung cancer by combined application of diabetes drug metformin and anti-PD-1 antibody, as we focused on the effect of functional augmentation of immunocompetent cells by metformin, and the effect of canceling the immune tolerance by anti-PD-1 antibody. We evaluated the function of lymphocytes in peripheral blood and tumor tissue in cancer patients. We cultured peripheral monocytes and tumor-infiltrating T cells with or without metformin, and stimulated T cells in a non-specific manner. We confirmed the increase of the production of cytokines by T cells. We also evaluated the anti-tumor effect by metformin-treated T cells plus anti-PD-1 antibody, and biomarkers that predict the anti-tumor effect by metformin-treated T cells plus anti-PD-1 antibody.

Academic Significance and Societal Importance of the Research Achievements

難治性疾患の一つである肺癌において、腫瘍免疫担当細胞の機能増強作用を有するメトホルミンと、近年免疫療法として注目されている抗PD-1抗体を組み合わせることによる新規治療法の開発に繋がる成果と考えられ、悪性腫瘍の中でも日本をはじめ世界の多くの国で死亡者数が多い肺癌の治療成績を改善するために、社会的意義が大きい成果と考えられる。

Research Products

• [Presentation] 2型糖尿病治療薬メトホルミンのヒト末梢血 CD8 T細胞への影響 (2018)
  • Author(s): 渡邉 元嗣、榮川 伸吾、豊岡 伸一、鵜殿 平一郎
  • Organizer: 第22回日本がん免疫学会総会
• [Presentation] Metformin improves immune function of exhausted peripheral CD8+ T cells derived from cancer patients (2017)
  • Author(s): Mototsugu Watanabe, Shingo Eikawa, Kazuhiko Shien, Hiromasa Yamamoto, Tadahiko Shien, Junichi Soh, Hiroyoshi Doihara, Shinichi Toyooka, Shinichiro Miyoshi, Heiichiro Udono
  • Organizer: AACR Annual Meeting 2017
  • Int'l Joint Research
• [Presentation] 2型糖尿病治療薬メトホルミンのヒト末梢血CD8 T細胞への影響 (2016)
  • Author(s): 渡邊元嗣、榮川伸吾、友信奈保子、野島一郎、木村裕司、上原健敬、國定勇希、豊岡伸一、鵜殿平一郎
  • Organizer: 第20回日本がん免疫学会総会
  • Place of Presentation: 大坂
  • Year and Date: 2016-07-27
• [Presentation] Metformin improves multiple cytokine producing ability of exhausted peripheral CD8+T cells of cancer patients. (2016)
  • Author(s): Watanabe M, Eikawa S, Takenori U, Kunisada Y, Toyota S, Miyoshi S, Udono H
  • Organizer: AACR Annual Meeting 2016
  • Place of Presentation: New Orleans, USA
  • Year and Date: 2016-04-16
  • Int'l Joint Research