Development of complehensive cancer immune cell therapies to overcome immune tolerance

• Project/Area Number: 18K08615
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 55020:Digestive surgery-related
• Research Institution: Shiga University of Medical Science
• Principal Investigator: Mekata Eiji 滋賀医科大学, 医学部, 教授 (80314152)
• Co-Investigator(Kenkyū-buntansha): 村田 聡 滋賀医科大学, 医学部, 講師 (90239525) ; 三宅 亨 滋賀医科大学, 医学部, 講師 (70581924) ; 谷 眞至 滋賀医科大学, 医学部, 教授 (60236677)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 免疫寛容 / 抗腫瘍免疫 / 複合的免疫療法 / OX40 / LAP / PD-1 / PD-L2 / 癌免疫細胞療法 / CTL / TGF-β陽性細胞除去カラム / OX40補助刺激 / 免疫チェックポイント阻害剤 / 抗PD-L2抗体 / がん免疫細胞治療 / T細胞補助刺激 / 免疫チェックポイント阻害薬 / エフェクター機能増強 / LAP陽性細胞吸着カラム / 癌免疫治療 / 細胞免疫治療 / 抗体治療 / 免疫チェックポイント / 制御性T細胞

Outline of Final Research Achievements

We conducted this research to establish a cancer antigen-specific CTL therapy that can overcome immune tolerance using the removal of TGF-β-producing immunosuppressive cells by LAP adsorption column, the function of CTL enhancing and regulatory T cell function inhibiting effects by OX40 costimulation, T cell costimulatory function by mB7-DC-Fc, or, the immune checkpoint inhibitory effect by PD-1 blocker.
CTL induction in an immunosuppressive cell-removed environment was effective. When LAP-T cells were induced with cancer antigen-specific CTL under cancer antigen stimulation and OX40-assisted stimulation, the transferred CTL maintained antitumor immune activity even under cancer antigen-specific immune tolerance and rejected the tumor. In addition, CTL induction by B7-DC costimulation or PD-1 inhibition was effective in maintaining CTL function under immune tolerance.

Academic Significance and Societal Importance of the Research Achievements

ペプチドワクチン療法や細胞傷害性Tリンパ球（CTL）移入療法などがヒト癌免疫治療に臨床応用されてきたが、満足のいく臨床成果は得られていない。生体では癌抗原（自己抗原）に対する免疫寛容（トレランス）が働くために、癌抗原特異的CTLを細胞移入しても、生体のトレランス機能に負け、CTLは抗腫瘍作用を失う。したがって、本研究で開発した免疫トレランスを打ち破る方法は、ヒト癌免疫治療を成功へと導く鍵となるであろう。本研究で明らかとなった有効な免疫作用を複合させたCTL誘導により、さらに強力なCTL細胞療法の開発が可能となる。

Research Products

• [Journal Article] In vivo antitumor function of tumor antigen-specific CTLs generated in the presence of OX40 co-stimulation in vitro (2018)
  • Author(s): Pham Minh Ngoc、Murata Satoshi、Kitamura Naomi、Ueki Tomoyuki、Kojima Masatsugu、Miyake Toru、Takebayashi Katsushi、Kodama Hirokazu、Mekata Eiji、Tani Masaji
  • Journal Title: International Journal of Cancer Volume: 142 Issue: 11 Pages: 2335-2343
  • DOI: 10.1002/ijc.31244
  • Peer Reviewed
• [Presentation] Tumor Ag-specific CTL generation from tumor-associated lymphocytes in malignant ascites of peritoneal metastases (2020)
  • Author(s): Masatsugu Kojima, Satoshi Murata, Miyuki Shimoji, Andreas Michael Sihombing, Naomi Kitamura, Tomoyuki Ueki, Mina Kitamura, Katsushi Takebayashi, Hirokazu Kodama, Aya Tokuda, Toru Miyake, Eiji Mekata, Masaji Tani
  • Organizer: 第79回日本癌学会学術総会
• [Presentation] Therapeutic strategy based on the mechanism of peritoneal relapse after surgery for gastric cancer (2020)
  • Author(s): Satoshi Murata, Katsushi Takebayashi, Tsuyoshi Yamaguchi, Sachiko Kaida, Ken Ishikawa, Hirokazu Kodama, Miyuki Shimoji, Andreas Michael Sihombing, Masatsugu Kojima, Toru Miyake, Hiroya Iida, Tomoyuki Ueki, Mina Kitamura, Aya Tokuda, Eiji Mekata, Masaji Tani
  • Organizer: 第79回日本癌学会学術総会
• [Presentation] Effect of hyperthermia on the cancer stem-like cells (2020)
  • Author(s): Miyuki Shimoji, Satoshi Murata, Andreas Michael Sihombing, Katsushi Takebayashi, Hirokazu Kodama, Masatsugu Kojima, Tomoyuki Ueki, Naomi Kitamura, Mina Kitamura, Aya Tokuda, Toru Miyake, Eiji Mekata, Masaji Tani.
  • Organizer: 第79回日本癌学会学術総会
• [Presentation] CD44-enriched cancer stem-like cells as a source of peritoneal metastasis from gastric cancer (2020)
  • Author(s): Andreas Michael Sihombing, Satoshi Murata, Miyuki Shimoji, Katsushi Takebayashi, Hirokazu Kodama, Masatsugu Kojima, Tomoyuki Ueki, Naomi Kitamura, Mina Kitamura, Aya Tokuda, Toru Miyake, Eiji Mekata, Masaji Tani
  • Organizer: 第79回日本癌学会学術総会
• [Presentation] 細胞移入後に担癌生体内で増殖できる腫瘍特異的CTL細胞療法 (2018)
  • Author(s): 村田 聡、Pham Minh Ngoc、北村 直美、河合 由紀、梅田 朋子、目片 英治、森 毅、冨田 香、北村 美奈、田中 彰恵、清水 智治、谷 眞至
  • Organizer: 第26回日本乳癌学会学術総会