Combined effects of co-stimulatory molecule gene transfer and radiotherapy on immune checkpoint inhibitors

• Project/Area Number: 19H03804
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 56050:Otorhinolaryngology-related
• Research Institution: Kobe University
• Principal Investigator: Ken-ichi Nibu 神戸大学, 医学研究科, 教授 (20251283)
• Co-Investigator(Kenkyū-buntansha): 井之口 豪 神戸大学, 医学部附属病院, 准教授 (10457046) ; 上原 奈津美 神戸大学, 医学部附属病院, 助教 (40570502) ; 大月 直樹 神戸大学, 医学研究科, 准教授 (40343264)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥16,380,000 (Direct Cost: ¥12,600,000、Indirect Cost: ¥3,780,000); Fiscal Year 2021: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2020: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2019: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000)
• Keywords: 扁平上皮癌 / 免疫チェックポイント阻害剤 / 共刺激因子 / B7 / CD90 / CD80 / 遺伝子導入 / 頭頸部癌 / B7遺伝子 / 免疫チェッックポイント阻害薬 / 共刺激分子 / 抗PD-1抗体 / 頭頸部がん / 放射線治療 / 遺伝子治療

Outline of Research at the Start

本研究は、手術、放射線治療、化学療法、分子標的薬に次ぐ、新たな治療法である免疫チェッックポイント阻害剤を活用する併用療法の開発を目指し、免疫チェックポイント阻害剤や放射線治療との併用効果とその根拠となる作用機序を明らかとすることを目標とする。
１．免疫チェックポイント阻害剤と共刺激分子の遺伝子導入の併用効果
２．免疫チェックポイント阻害剤と放射線療法の併用効果
３．免疫チェックポイント阻害剤と化学放射線療法の併用効果
４．免疫チェックポイント阻害剤と化学放射線療法、共刺激分子の遺伝子導入の併用効果

Outline of Final Research Achievements

In our previous study, we reported that gene transfer of the B7 molecule (CD80) into a mouse squamous cell carcinoma model efficiently amplified tumor-specific CTLs and had a growth inhibitory effect not only on tumor cells expressing the B7 molecule (CD 80) but also on non-transfected tumor cells.
In this study, we examined the combined effects of immune checkpoint inhibitors and gene transfer of the co-stimulatory molecule B7 molecule (CD 80) using a mouse squamous cell carcinoma model. The combination of both treatment strategies resulted in almost complete disappearance of tumors transplanted into mice and a significant combined effect.

Academic Significance and Societal Importance of the Research Achievements

マウスに移植した扁平上皮がん腫瘍細胞にアデノウイルスベクターを用いて共刺激分子B7(CD80)を導入することにより免疫チェックポイント阻害剤の効果を有意に増強することを示すことができた。免疫チェックポイント阻害剤と共刺激分子の併用という新たな治療法の開発につながる成果が得られた。本治療法が実用化されることが望まれる。

Research Products

• [Journal Article] Real-world safety and effectiveness of nivolumab for recurrent or metastatic head and neck cancer in Japan: a post-marketing surveillance (2021)
  • Author(s): Tahara Makoto、Kiyota Naomi、Nibu Ken-ichi、Akamatsu Ayumi、Hoshino Tomohiro、Hayashi Ryuichi
  • Journal Title: International Journal of Clinical Oncology Volume: 26 Issue: 9 Pages: 1619-1627
  • DOI: 10.1007/s10147-021-01949-1
  • Peer Reviewed / Open Access
• [Journal Article] Oncogenic E6 and/or E7 proteins drive proliferation and invasion of human papilloma virus?positive head and neck squamous cell cancer through upregulation of Ror2 expression (2021)
  • Author(s): Avincsal Mehmet、Kamizaki Koki、Jimbo Naoe、Shinomiya Hirotaka、Nibu Ken-Ichi、Nishita Michiru、Minami Yasuhiro
  • Journal Title: Oncology Reports Volume: 46 Issue: 1 Pages: 148-148
  • DOI: 10.3892/or.2021.8099
  • Peer Reviewed / Open Access
• [Journal Article] Pathological evaluation of tumor grade for salivary adenoid cystic carcinoma: A proposal of an objective grading system (2021)
  • Author(s): Morita N, Murase T, Ueda K, Nagao T, Kusafuka K, Nakaguro M, Urano M, Taguchi KI, Yamamoto H, Kano S, Tada Y, Tsukahara K, Okami K, Onitsuka T, Fujimoto Y, Kawakita D, Sakurai K, Nagao T, Hanai N, Kawata R, Hato N, Otsuki N, Nibu KI, Inagaki H.
  • Journal Title: Cancer Science Volume: 112(3) Issue: 3 Pages: 1184-1195
  • DOI: 10.1111/cas.14790
  • Peer Reviewed / Open Access
• [Journal Article] Treatment outcomes of transoral robotic and non-robotic surgeries to treat oropharyngeal, hypopharyngeal, and supraglottic squamous cell carcinoma: A multi-center retrospective observational study in Japan (2021)
  • Author(s): Sano Daisuke、Shimizu Akira、Tateya Ichiro、Fujiwara Kazunori、Mori Terushige、Miyamoto Shunsuke、Nishikawa Daisuke、Terada Tomonori、Yasumatsu Ryuji、Ueda Tsutomu、Matsumoto Fumihiko、Kishimoto Yo、Maruo Takashi、Fujimoto Yasushi、Tsukahara Kiyoaki、Yoshimoto Seiichi、Nibu Ken-ichi、Oridate Nobuhiko
  • Journal Title: Auris Nasus Larynx Volume: 48 Issue: 3 Pages: 502-510
  • DOI: 10.1016/j.anl.2021.01.024
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Oncolytic effect of Midkine promoter-based conditionally replicating adenoviruses expressing EGFR siRNA in head and neck squamous cancer cell line T891 (2020)
  • Author(s): Uehara Natsumi、Otsuki Naoki、Kubo Mie、Kitamoto Junko、Kojima Yasutaka、Teshima Masanori、Shinomiya Hirotaka、Shirakawa Toshiro、Nibu Ken-ichi
  • Journal Title: Cancer Reports Volume: 2 Issue: 3
  • DOI: 10.1002/cnr2.1231
  • Peer Reviewed / Open Access
• [Journal Article] Optimization of therapeutic strategy for p16‐positive oropharyngeal squamous cell carcinoma: Multi‐institutional observational study based on the national Head and Neck Cancer Registry of Japan (2020)
  • Author(s): Saito Yuki、et al.
  • Journal Title: Cancer Volume: 126 Issue: 18 Pages: 4177-4187
  • DOI: 10.1002/cncr.33062
  • Peer Reviewed / Open Access
• [Journal Article] Effect of tumor burden and growth rate on treatment outcomes of nivolumab in head and neck cancer (2020)
  • Author(s): Suzuki C.、Kiyota N.、Imamura Y.、Rikitake J.、Sai S.、Koyama T.、Hyogo Y.、Nagatani Y.、Funakoshi Y.、Toyoda M.、Otsuki N.、Nibu KI.、Minami H.
  • Journal Title: International Journal of Clinical Oncology Volume: 25 Issue: 7 Pages: 1270-1277
  • DOI: 10.1007/s10147-020-01669-y
  • Peer Reviewed