Development of antitumor immunological agent using mycobacterial surface glycolipids as lead compounds.

• Project/Area Number: 18H02934
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 56030:Urology-related
• Research Institution: University of Tsukuba
• Principal Investigator: NISHIYAMA Hiroyuki 筑波大学, 医学医療系, 教授 (20324642)
• Co-Investigator(Kenkyū-buntansha): 宮崎 淳 国際医療福祉大学, 医学部, 主任教授 (10550246) ; 神鳥 周也 筑波大学, 医学医療系, 講師 (50707825) ; 小島 崇宏 筑波大学, 医学医療系, 准教授 (40626892) ; 河合 弘二 筑波大学, 医学医療系, 講師 (90272195)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥17,160,000 (Direct Cost: ¥13,200,000、Indirect Cost: ¥3,960,000); Fiscal Year 2021: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2020: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2019: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2018: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000)
• Keywords: 膀胱癌 / BCG / ミコール酸 / TDM / リポソーム / 癌免疫療法 / 脂質 / リンパ球 / 癌免疫 / トレハロース 6,6′-ジミコラート / コードファクター / 抗酸菌 / 腫瘍免疫 / 感染免疫 / 細胞壁成分 / trehalose-6 6’-dimycolate / 抗酸菌表層糖脂質 / mycobacterium bovis BCG

Outline of Final Research Achievements

Intravesical infusion therapy of Mycoabcterium bovis bacillus Calmette-Guerin (BCG) is widely used for the prevention of postoperative recurrence of non-muscle invasive bladder cancer .The most important immunostimulant of BCG bacteria is trehalose-6 6'-dimycolate (TDM), which is composed of mycolic (MA) acid, whcich is a long-chain fatty acid unique to antacid bacteria. Since TDM has strong hydrophobicity, we made it into a hydrophilic liposome and we verified its anti-tumour activity. We also revealed changes in the anti-tumour activity of TDM liposome due to the different subclasses of MAs that compose TDM.

Academic Significance and Societal Importance of the Research Achievements

TDMリポソーム製剤を最適化し、抗腫瘍活性が最大となるように調整することで、新しい癌免疫療法に向けたシーズとなる。TDMリポソームは非生菌製剤であることから、BCG菌のような尿路感染症や、全身播種性感染といった重篤な副作用が起こらない。また、生菌製剤のようなバイオハザード管理の必要もなく、通常の薬剤と同様に管理、供給運搬が可能である。感染の可能性がないため、静脈内投与も含めたあらゆる投与方法が可能である。したがって、TDMリポソーム製剤は安全性と有効性の点で優れた治療薬開発へつながる見込みが高い。本研究は最も臨床的有用性の高い、安定した毒性の低い安価な癌免疫治療薬として期待される。

Research Products

• [Int'l Joint Research] Diagnostig 社(英国)
• [Journal Article] The liposome of trehalose dimycolate extracted from M. bovis BCG induces antitumor immunity via the activation of dendritic cells and CD8+ T cells (2021)
  • Author(s): Shiga Masanobu、Miyazaki Jun、Tanuma Kozaburo、Nagumo Yoshiyuki、Yoshino Takayuki、Kandori Shuya、Negoro Hiromitsu、Kojima Takahiro、Tanaka Ryota、Okiyama Naoko、Fujisawa Yasuhiro、Watanabe Miyuki、Yamasaki Sho、Kiyohara Hideyasu、Watanabe Makoto、Sato Taka-aki、Tahara Hideaki、Nishiyama Hiroyuki、Yano Ikuya
  • Journal Title: Cancer Immunology, Immunotherapy Volume: - Issue: 9 Pages: 2529-2543
  • DOI: 10.1007/s00262-021-02870-2
  • Peer Reviewed
• [Journal Article] The resonance(R) metallic ureteral stent in the treatment of malignant ureteral obstruction: a prospective observational study. (2019)
  • Author(s): Miyazaki J, Onozawa M, Takahashi S, Maekawa Y, Yasuda M, Wada K, Maeda Y, Masaki T, Yamaguchi A, Suzuki M, Sakai Y, Kimura T, Takai M, Seike K, Hashimoto T, Yamamoto S.
  • Journal Title: BMC Urol. Volume: 27;19(1) Issue: 1 Pages: 137-137
  • DOI: 10.1186/s12894-019-0569-y
  • Peer Reviewed / Open Access
• [Journal Article] Cationized liposomal keto-mycolic acids isolated from Mycobacterium bovis bacillus Calmette-Gu?rin induce antitumor immunity in a syngeneic murine bladder cancer model (2019)
  • Author(s): Yoshino Takayuki、Miyazaki Jun、Kojima Takahiro、Kandori Shuya、Shiga Masanobu、Kawahara Takashi、Kimura Tomokazu、Naka Takashi、Kiyohara Hideyasu、Watanabe Miyuki、Yamasaki Sho、Akaza Hideyuki、Yano Ikuya、Nishiyama Hiroyuki
  • Journal Title: PLOS ONE Volume: 14 Issue: 1 Pages: 1-19
  • DOI: 10.1371/journal.pone.0209196
  • Peer Reviewed / Open Access
• [Presentation] The liposome of trehalose dimycolate from M.bovis BCG induce antitumor immunity via dendritic cells and CD8+ T cells (2020)
  • Author(s): 志賀正宣、宮﨑淳、西山博之、矢野郁也
  • Organizer: 日本癌学会
• [Presentation] Antitumor effect of cationic liposome incorporating keto-mycolic acid from Mycobacterium bovis bacillus Calmette-Guerin in mouse model. (2018)
  • Author(s): Takayuki Yoshino, Jun Miyazaki, Takahiro Kojima, Shuya Kandori, Hideyuki Akaza, Ikuya Yano, Hiroyuki Nishiyama
  • Organizer: ASCO-GU
  • Int'l Joint Research
• [Patent(Industrial Property Rights)] 非結核性抗酸菌感染症診断用キット、リポソーム (2019)
  • Inventor(s): 西山博之、志賀正宣、渡邊真広、宮﨑淳、矢野郁也
  • Industrial Property Rights Holder: 西山博之、志賀正宣、渡邊真広、宮﨑淳、矢野郁也
  • Industrial Property Rights Type: 特許
  • Filing Date: 2019