Preclinical evaluation of the antitumor effect of cancer immunotherapy augmented by antiangiogenic agent in malignant pleural mesothelioma

• Project/Area Number: 19K17654
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53030:Respiratory medicine-related
• Research Institution: Hyogo Medical University
• Principal Investigator: Negi Yoshiki 兵庫医科大学, 医学部, 助教 (70814515)
• Project Period (FY): 2019-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2020: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000); Fiscal Year 2019: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 悪性胸膜中皮腫 / 抗PD-1抗体 / 血管新生阻害薬 / がん免疫療法 / 血管新生阻害剤

Outline of Research at the Start

2018年より抗PD-1抗体Nivolumabが再発MPMに対して実臨床でも使用できるようになった。この事は、がん免疫療法が長らく新たな治療法のなかったMPM症例においてもbreakthroughとなり得る事を示唆している。MPM治療におけるがん免疫療法の更なる向上のため、血管新生阻害剤と抗PD-1抗体の併用療法についてのpreclinical studyと実臨床でのpilot studyを行う。

Outline of Final Research Achievements

Malignant pleural mesothelioma is refractory malignant neoplasm with extreme poor prognosis. Recently, anti-programmed cell death (PD)-1 antibody, nivolumab, has been approved for the treatment of relapsed-MPM, and actually exerts remarkable antitumor effect in certain cases. Thus, anticancer immunotherapy is expected to be a breakthrough therapy in MPM as well as lung cancer.
In the present study, we established mouse subcutaneous MPM xenograft model and showed that antiangiogenic agent, nintedanib, enhanced antitumor immunity against MPM cells induced by anti PD-1 antibody via through activating cytotoxic T cell not only numerically but also functionally. These results indicate that antiangiogenic agent is a promising candidate as a novel molecular targeted therapy in MPM.

Academic Significance and Societal Importance of the Research Achievements

悪性胸膜中皮腫は稀少がんの一種ではあるが、本邦における過去のアスベスト使用状況から今後も患者数、死亡者数は増加すると予想されている。2018年に世界に先駆けて免疫チェックポイント阻害薬ニボルマブが、再発悪性胸膜中皮腫に保険適応となった。がん免疫療法が今後の中皮腫治療の軸となっていくと予想され、その効果をどうすれば高める事ができるかを検討する事は非常に重要である。申請者は血管新生阻害薬と免疫チェックポイント阻害薬の併用が従来の免疫チェックポイント阻害薬単剤での効果を上回る可能性がを見出した。今回使用した血管新生阻害薬は実臨床で用いられており、速やかに臨床試験等の計画・実行につながる。

Research Products

• [Journal Article] Tumor‐associated macrophage‐derived inflammatory cytokine enhances malignant potential of malignant pleural mesothelioma (2020)
  • Author(s): Horio Daisuke、Minami Toshiyuki、Kitai Hidemi、Ishigaki Hirotoshi、Higashiguchi Yoko、Kondo Nobuyuki、Hirota Seiichi、Kitajima Kazuhiro、Nakajima Yasuhiro、Koda Yuichi、Fujimoto Eriko、Negi Yoshiki、Niki Maiko、Kanemura Shingo、Shibata Eisuke、Mikami Koji、Takahashi Ryo、Yokoi Takashi、Kuribayashi Kozo、Kijima Takashi
  • Journal Title: Cancer Science Volume: - Pages: 2895-2906
  • DOI: 10.1111/cas.14523
  • Peer Reviewed / Open Access
• [Journal Article] Adenosine Deaminase in Pleural Effusion and Its Relationship with Clinical Parameters in Patients with Malignant Pleural Mesothelioma (2020)
  • Author(s): Nakajima Yasuhiro、Kuribayashi Kozo、Ishigaki Hirotoshi、Tada Akio、Negi Yoshiki、Minami Toshiyuki、Takahashi Ryo、Doi Hiroshi、Kitajima Kazuhiro、Yokoi Takashi、Kijima Takashi
  • Journal Title: Cancer Investigation Volume: 38 Pages: 356-364
  • DOI: 10.1080/07357907.2020.1776313
  • Peer Reviewed
• [Presentation] Inflammatory cytokine derived from inflammasome in tumor-associated macrophages enhances malignant potential of malignant pleural mesothelioma (2020)
  • Author(s): Daisuke Horio, Toshiyuki Minami, Hidemi Kitai, Hirotoshi Ishigaki, Yasuhiro Nakajima, Yoshiki Negi, Maiko Niki, Eisuke Shibata, Koji Mikami, Ryo Takahashi, Takashi Yokoi, Kozo Kuribayashi, and Takashi Kijima
  • Organizer: The 3rd International Cancer Research Symposium
  • Int'l Joint Research