Combination therapy of ultrasound irradiation and immune-check point inhibitors on prostate cancer

• Project/Area Number: 21K20990
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund
• Review Section: 0906:Surgery related to the biological and sensory functions and related fields
• Research Institution: Kobe University
• Principal Investigator: Maeda Koki 神戸大学, 医学部附属病院, 医員 (20899843)
• Project Period (FY): 2021-08-30 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000); Fiscal Year 2022: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 超音波照射 / 免疫チェックポイント阻害剤 / 前立腺癌

Outline of Research at the Start

我々は予備検討にて前立腺癌細胞株に高強度超音波照射を行い、癌細胞の細胞膜を損傷させ、アポトーシスを誘導して癌増殖を直接抑制できることを証明した。本研究では超音波照射による細胞膜損傷に着眼し、癌細胞からの癌抗原放出を起点とした癌抗原特異的免疫応答の賦活効果を検討する。現在、前立腺癌は免疫チェックポイント阻害薬に代表される免疫療法の効果が乏しく、その解決のカギは癌抗原特異的免疫応答の獲得にあると思われる。本研究では上記免疫賦活効果の概念実証を目的とし、主に前立腺癌マウスモデルを用いて、超音波照射と免疫チェックポイント阻害薬を併用してその相乗的治療効果について検討する。

Outline of Final Research Achievements

We have investigated the antitumor effects of high-intensity ultrasound irradiation on prostate cancer cells, as well as the synergistic effects of the treatment in combination with immune checkpoint inhibitors in animal experiments. In cell experiments, it was shown that the therapeutic effect of ultrasound irradiation is manifested within a short time after irradiation, and that the main mechanism is the induction of apoptosis by transient disruption of cell membranes. In animal experiments, the combination of ultrasound irradiation tails and immune checkpoint inhibitors was found to enhance the anti-tumor effect.

Academic Significance and Societal Importance of the Research Achievements

前立腺癌は男性の悪性疾患の中で最も高い罹患率となっている。手術、放射線、ホルモン治療や抗がん剤などの優れた治療方法がある一方で、それぞれの治療による合併症がある。また、前立腺癌は免疫チェックポイント阻害剤による治療効果が限定的であることも知られている。
今回の研究により、超音波照射が前立腺癌の局所治療の選択肢となる可能性を示せただけでなく、免疫チェックポイント阻害剤と超音波照射の併用により全身治療の選択肢となる可能性も示すことが出来た。

Research Products

• [Journal Article] Proapoptotic effect of non-thermal pulsed ultrasound on prostate cancer cells in a nude mouse model (2023)
  • Author(s): Koki Maeda, Katsumi Shigemura, Fuuka Hayashi, Yuki Kan, Aya Hiraoka, Atomu Yamaguchi, Minori Ueda, Yong-Ming Yang, Noriaki Maeshige, Tooru Ooya, Yuzo Nakano, Masato Fujisawa
  • Journal Title: The Prostate Volume: in-press
  • Peer Reviewed
• [Journal Article] Combined Treatment with Ultrasound and Immune Checkpoint Inhibitors for Prostate Cancer (2022)
  • Author(s): Fuuka Hayashi, Katsumi Shigemura, Koki Maeda, Aya Hiraoka, Noriaki Maeshige, Tooru Ooya, Shian-Ying Sung, Yong-Ming Yang, Masato Fujisawa
  • Journal Title: Journal of Clinical Medicine Volume: 11 Issue: 9 Pages: 2448-2448
  • DOI: 10.3390/jcm11092448
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Combined Treatment with ultrasound and immune checkpoint inhibitors for prostate cancer (2022)
  • Author(s): Fuuka Hayashi,Katsumi Shigemura, Koki Maeda, Noriaki Maeshige, Aya Hiraoka, Tooru Ooya,Yong-Ming Yang, and Masato Fujisawa
  • Organizer: American Urological Association. 2022.
  • Int'l Joint Research
• [Presentation] The anti-tumor effect of ultrasound irradiation for the prostate cancer (2021)
  • Author(s): Koki Maeda, Katsumi Shigemura, Koichi Kitagawa, Fuuka Hayashi, Aya Hiraoka, Atomu Yagamuchi, Yong-Ming Yang, Noriaki Maeshige, Takeshi Kondo, Yuzo Nakano, Masato Fujisawa
  • Organizer: The 37th KOREA-JAPAN Urological Congress
  • Int'l Joint Research