HLA as a biomarker for Immune checkpoint inhibitos

• Project/Area Number: 17K08952
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Applied pharmacology
• Research Institution: Kobe University
• Principal Investigator: Minami Hironobu 神戸大学, 医学研究科, 教授 (60450574)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2019: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2018: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2017: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
• Keywords: 腫瘍内科学 / 免疫チェックポイント阻害 / HLA / 免疫関連有害事象 / 臨床薬理学 / 免疫チェックポイント阻害薬 / マイマーカー / 免疫チャックポイント阻害薬 / バイオマーカー / 免疫チェックポイント / がん

Outline of Final Research Achievements

Relationship between immune-related adverse event (irAE) induced by immune checkpoint inhibitors and HLA was investigated in patients with various cancers including head and neck cancer, gastric cancer, and melanoma. HLA was analyzed in 69 patients including 5 patients treated with the combination of anti-PD-1 antibody and anti-CTLA-4 antibody from February, 2018 to February, 2020.
Various irAEs were observed, and 80% of patients treated with the combination of anti-PD-1 antibody and anti-CTLA-4 antibody developed irAEs in contrast to 21% in patients treated with anti-PD-1 antibody as a single agent.
Statistically significant association between development of irAEs and certain HLAs were identified.

Academic Significance and Societal Importance of the Research Achievements

本研究において、抗PD-1抗体薬単独では免疫関連有害事象は21%にみられたのに対し、抗PD-1抗体と抗CTLA-4抗体の併用では80%に見られた。これは抗PD-1抗体の単独と抗CTLA-4抗体との併用では免疫関連有害事象に差があることを確認したもので、今後の治療選択の際に参考になる。また、今回、新たに免疫関連有害事象の発症と関連するHLAを同定したことは、さらに研究を発展させることにより、治療前にHLAを検査し免疫関連有害事象の発症リスクを予測し治療法の選択に活用する個別化治療の開発につながる。

Research Products

• [Journal Article] Efficacy and safety of nivolumab in Japanese patients with uterine cervical cancer, uterine corpus cancer, or soft tissue sarcoma: multicenter, opemn-label phase 2 trial (2019)
  • Author(s): Tamura K, Hasegawa K, Katsumata N, Matsumoto K, Mukai H, Takahashi S, Nomura H, Minami H.
  • Journal Title: Cancer Sci Volume: 110 Issue: 9 Pages: 2894-2904
  • DOI: 10.1111/cas.14148
  • Peer Reviewed
• [Journal Article] Long-term follow up of nivolumab in previously untreated Japanese patients with advanced or recurrent malignant melanoma. (2019)
  • Author(s): Yamazaki N, Kiyohara Y, Uhara H, Uehara J, Fujisawa Y, Takenouchi T, Otsuka M, Uchi H, Ihn H, Hatsumichi M, Minami H.
  • Journal Title: Cancer Sci Volume: 110 Issue: 6 Pages: 1995-2003
  • DOI: 10.1111/cas.14015
  • NAID: 120006653247
• [Journal Article] Expression of programmed death-1 in sentinel lymph nodes of breast cancer. (2017)
  • Author(s): Tatara T, Mukohara T, Shimono Y, Yamasaki T, Imamura Y, Funakoshi Y, Toyoda M, Kiyota N, Takao S, Kono S, Kakeji Y, Minami H
  • Journal Title: J Surg Oncol. Volume: Epub ahead of print Issue: 6 Pages: 2017-2017
  • DOI: 10.1002/jso.24937
  • Peer Reviewed
• [Journal Article] Efficacy and safety of nivolumab in Japanese patients with previously untreated advanced melanoma: A phase II study (2017)
  • Author(s): Yamazaki Naoya、Kiyohara Yoshio、Uhara Hisashi、Uehara Jiro、Fujimoto Manabu、Takenouchi Tatsuya、Otsuka Masaki、Uchi Hiroshi、Ihn Hironobu、Minami Hironobu
  • Journal Title: Cancer Sci Volume: 108 Issue: 6 Pages: 1223-1230
  • DOI: 10.1111/cas.13241
  • Peer Reviewed / Open Access