Basic Research on Novel Treatment for Dialysis Kidney Cancer Using Immune Checkpoint Molecular Antibodies

• Project/Area Number: 19K16807
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 50020:Tumor diagnostics and therapeutics-related
• Research Institution: Keio University
• Principal Investigator: Takamatsu Kimiharu 慶應義塾大学, 医学部(信濃町), 共同研究員 (00649874)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2021: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2020: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2019: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 腎細胞癌 / 腫瘍免疫微小環境 / LAG-3 / TIM-3 / TIGIT / 免疫チェックポイント阻害剤 / 免疫チェックポイント分子 / 薬物療法 / 透析腎癌 / 腫瘍微小環境

Outline of Research at the Start

進行透析腎癌は現在、確立された薬物療法がない。本研究では、透析腎癌における免疫チェックポイント分子PD-L3阻害薬とmTOR阻害薬の併用による新基地利用戦略の確立を目的とする。本研究では透析腎癌検体における、PD-L3、mTORの発現と臨床経過の関連の評価。両薬剤併用による殺細胞効果の評価。両薬剤の併用が、透析腎癌細胞株に及ぼす変化の遺伝子発現レベルでの検討を計画している。

Outline of Final Research Achievements

After evaluating the immune microenvironment in hemodialysis renal cell carcinoma, we found that PDL1 expression was higher in HD-renal carcinoma than in normal-type clear cell renal cell carcinoma, and reported this finding at the japanese pediatric urology annual conference.
Furthermore, in the process of analyzing the tumor immune microenvironment, PD-1/PD-L1 inhibitor-resistant cases have been became clinical unmet needs. Therefore, focusing on the expression status of next-generation checkpoint molecules, LAG-3, TIM-3, and TIGT, we found that the three molecules are mutually exclusive in renal cell carcinoma and that the background of the mutation is p53 gene mutation. We constructed and reported a new classification of renal cell carcinoma using these three novel molecules.

Academic Significance and Societal Importance of the Research Achievements

本研究で明らかになった透析腎癌の免疫環境の特徴は透析腎癌において免疫チェックポイント阻害剤の効果が高いことを示唆するものであり、臨床上有意義である。
また、次世代チェックポイント分子が腎細胞癌で相互排他性を示すことは、現在開発中の次世代免疫チェックポイント阻害剤の治療薬選択につながる可能性があり、テイラーメイド医療による薬剤の有効性の最大化につながる。さらに、高額な新規薬剤の有効利用の点から医療経済への寄与が期待される。

Research Products

• [Journal Article] Profiling the inhibitory receptors LAG-3, TIM-3, and TIGIT in renal cell carcinoma reveals malignancy (2021)
  • Author(s): Kimiharu Takamatsu
  • Journal Title: Nature Communications Volume: 12 Issue: 1 Pages: 5547-5547
  • DOI: 10.1038/s41467-021-25865-0
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 次世代免疫チェックポイント分子(LAG-3, TIM-3, TIGIT)による 腎細胞がん新規分類の臨床的有用性 (2021)
  • Author(s): 髙松公晴
  • Organizer: 第109回日本泌尿器科学会総会
• [Presentation] Xp11.2転座型腎細胞癌における腫瘍周囲微小免疫環境の評価 (2020)
  • Author(s): 高松公晴
  • Organizer: 第29回日本小児泌尿器科学会
• [Presentation] The change of serum C-reactive protein levels during molecular-targeted treatments could predict the response to anti-PD-1 treatment in metastatic renal cell carcinoma patients (2020)
  • Author(s): Takamatsu Kimiharu
  • Organizer: American Society of Clinical Oncology Annual meeting 2020
  • Int'l Joint Research
• [Presentation] Novel prognostification model for clear cell renal cell carcinoma: Proposing the immune-based clustering algorithm using future immune-checkpoint targets (2020)
  • Author(s): Takamatsu Kimiharu
  • Organizer: 114th American Urological Association Annual Meeting: Washington D.C., USA
  • Int'l Joint Research
• [Presentation] Xp11.2転座型腎細胞癌においてInterleukin-6はprogrammed cell death-1 ligand(PDL1)発現を誘導する (2019)
  • Author(s): 髙松公晴
  • Organizer: 第28回小児泌尿器科学会総会
• [Presentation] Clinical impact of serum C-reactive protein levels in metastatic renal-cell carcinoma patients treated by second-line molecular targeted therapies. (2019)
  • Author(s): 髙松公晴
  • Organizer: American Society of Clinical Oncology Annual meeting 2019
  • Int'l Joint Research