Identification of predictive biomarkers for immune checkpoint inhibitors using T cell receptor repertoire analysis

• Project/Area Number: 18K09133
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 56030:Urology-related
• Research Institution: Osaka University
• Principal Investigator: Kato Taigo 大阪大学, 医学系研究科, 助教 (70648021)
• Co-Investigator(Kenkyū-buntansha): 清谷 一馬 公益財団法人がん研究会, がんプレシジョン医療研究センター 免疫ゲノム医療開発プロジェクト, 主任研究員 (30433642) ; 植村 元秀 大阪大学, 医学系研究科, 講師 (40631015) ; 朝長 毅 国立研究開発法人医薬基盤・健康・栄養研究所, 医薬基盤研究所 創薬デザイン研究センター, 上級研究員 (80227644)
• Project Period (FY): 2018-04-01 – 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: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
• Keywords: 免疫チェ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阻害剤 / 泌尿器科癌 / TCRシーケンス / エクソソーム / 腎癌

Outline of Final Research Achievements

Immune checkpoint inhibitors (ICIs) are now widely used in several types of cancer. However, the response rate is limited and it is urgent to pursue novel non-invasive biomarkers of responses to ICI that allow the “early” determination of clinical benefits. We collected RNA from peripheral blood mononuclear cells (PMBC) before and after treatment with nivolumab, T cell receptor (TCR) repertoire analysis revealed that the responders to nivolumab showed an expansion of certain T cell clones even in the blood, as evidenced by the significant decrease in the TCR diversity index and increase in the number of expanded TCR clonotypes 1 month after treatment. We propose that global TCR repertoire analysis may allow identifying early surrogate biomarkers in the peripheral blood for predicting clinical responses to anti-PD-1 therapy.

Academic Significance and Societal Importance of the Research Achievements

今回の研究では、代表的なICIであるニボルマブ投与患者において、TCRレパトア解析によるパラメーターの変化が治療後早期奏効予測マーカーとなり得ることが示された。本研究成果は進行性腎細胞癌に限らず、ICIを利用する複数の癌腫に適応可能である。奏効予測マーカーを明らかにすることで、適切な患者選択が可能となり、大幅な医療費削減にも貢献できると考えられる。

Research Products

• [Journal Article] Peripheral T cell receptor repertoire features predict durable responses to anti-PD-1 inhibitor monotherapy in advanced renal cell carcinoma (2021)
  • Author(s): Kato T, Kiyotani K, Tomiyama E, Koh Y, Matsushita M, Hayashi Y, Nakano K, Ishizuya Y, Wang C, Hatano K, Kawashima A, Ujike T, Fujita K, Nonomura N, Uemura M.
  • Journal Title: OncoImmunology Volume: 10 Issue: 1 Pages: 1862948-1862948
  • DOI: 10.1080/2162402x.2020.1862948
  • Peer Reviewed / Open Access
• [Journal Article] A Potential Mechanism of Anticancer Immune Response Coincident With Immune-related Adverse Events in Patients With Renal Cell Carcinoma (2020)
  • Author(s): Kato T, Tomiyama E, Koh Y, Matsushita M, Hayashi Y, Nakano K, Ishizuya YU, Wang C, Hatano K, Kawashima A, Ujike T, Kawasaki K, Morii E, Gotoh K, Eguchi H, Kiyotani K, Fujita K, Nonomura N, Uemura M.
  • Journal Title: Anticancer Research Volume: 40 Issue: 9 Pages: 4875-4883
  • DOI: 10.21873/anticanres.14490
  • Peer Reviewed / Open Access
• [Presentation] 進行性腎細胞癌における免疫チェックポイント阻害剤早期奏効予測のための血液バイオマーカーの開発 (2020)
  • Author(s): 加藤大悟、冨山栄輔、洪陽子、松下慎、中野剛佑、林裕次郎、波多野浩士、河嶋厚成、氏家剛、藤田和利、清谷一馬、植村元秀、野々村祝夫
  • Organizer: 第23回日本免疫治療学会
• [Presentation] Elucidation of early predictive biomarker in urological cancer patients with immune checkpoint inhibitors using T cell receptor sequencing (2020)
  • Author(s): 加藤大悟、冨山栄輔、洪陽子、松下慎、中野剛佑、林裕次郎、波多野浩士、河嶋厚成、氏家剛、藤田和利、清谷一馬、植村元秀、野々村祝夫
  • Organizer: 第24回日本がん免疫学会総会
• [Presentation] T cell receptor sequencing predict early response for immune-check point inhibitors in urological cancer (2020)
  • Author(s): Taigo Kato, Eisuke Tomiyama, Yoko Koh, Makoto Matsusita, Yujiro Hayashi, Kosuke Nakano, Yu Ishizuya, Cong Wang, Koji Hatano, Atsunari Kawashima, Takeshi Ujike, Kazutoshi Fujita, Kazuma Kiyotani, Motohide Uemura, Norio Nonomura
  • Organizer: 第79回日本癌学会
• [Presentation] Elucidation of early predictive biomarker in urological cancer patients with immune checkpoint inhibitors using T cell receptor sequencing (2020)
  • Author(s): Taigo Kato, Kazuma Kiyotani, Eisuke Tomiyama, Yoko Koh, Makoto Matsusita, Yujiro Hayashi, Kosuke Nakano, Yu Ishizuya, Cong Wang, Koji Hatano, Atsunari Kawashima, Takeshi Ujike, Kazutoshi Fujita, Motohide Uemura, Norio Nonomura
  • Organizer: 第58回日本癌治療学会
• [Presentation] T細胞受容体レパトア解析を用いた免疫チェックポイント阻害剤早期奏効予測バイオマーカーの探索 (2020)
  • Author(s): 加藤大悟、冨山栄輔、洪陽子、松下慎、中野剛佑、林裕次郎、波多野浩士、河嶋厚成、氏家剛、藤田和利、清谷一馬、植村元秀、野々村祝夫
  • Organizer: 第108回日本泌尿器科学会総会
• [Presentation] Identification of early predictive biomarker for immune checkpoint inhibitors by T cell receptor repertoire analysis in advanced kidney cancer patients (2020)
  • Author(s): Taigo Kato, Kazuma Kiyotani, Eisuke Tomiyama, Yoko Koh, Makoto Matsusita, Yujiro Hayashi, Kosuke Nakano, Yu Ishizuya, Cong Wang, Koji Hatano, Atsunari Kawashima, Takeshi Ujike, Kazutoshi Fujita, Motohide Uemura, Norio Nonomura
  • Organizer: American Urological Association Annual Conference 2020
  • Int'l Joint Research