Role of intestinal flora on the antitumor immunity of oncolytic viruses

• Project/Area Number: 19H03434
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 49010:Pathological biochemistry-related
• Research Institution: Nagoya University
• Principal Investigator: Naoe Yoshinori 名古屋大学, 医学系研究科, 特任准教授 (50392048)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000); 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: ¥7,410,000 (Direct Cost: ¥5,700,000、Indirect Cost: ¥1,710,000)
• Keywords: 腫瘍溶解性ウイルス / C-REV / 腸内細菌叢 / 抗生物質 / 抗腫瘍効果 / 免疫 / 癌

Outline of Research at the Start

腫瘍溶解性ウイルスは腫瘍特異的に感染し、腫瘍を崩壊する。さらに、破壊された腫瘍が癌抗原を放出することにより癌免疫応答を惹起する。一方、腸内菌叢は腸管局所のみならず、全身的な免疫にも大きな影響を与えていることが明らかになりつつある。これらのことから、腫瘍溶解性ウイルスの効果に腸内細菌叢が影響することは容易に考えられるが、詳細な報告は全くない。本研究では、腸内細菌叢の変化による免疫反応の変化が、腫瘍溶解性ウイルスが惹起する癌免疫応答反応にどのように影響を与え、抗腫瘍効果をいかに調節するかを明らかにすることを目的に行う。

Outline of Final Research Achievements

Changes in the intestinal flora were observed by administration of C-REV to antibiotic-treated mice in the intraperitoneal transplant model and the subcutaneous transplant model. The antitumor effect of C-REV changes depending on the combination of the four antibiotics Ampicillin (A), Metronidazole (M), Neomycin (N), or Vancomycin (V), and the order of the effect is (large effect) AMNV = AMV > MNV > ANV = AMN (small effect). The difference in the bacterial flora of the mice by the antibiotic cocktail treatment was found, and a large change was observed in the bacterial flora with and without the antibiotic cocktail treatment.

Academic Significance and Societal Importance of the Research Achievements

腸内細菌叢の変化により化学療法、免疫チェックポイント阻害剤の抗腫瘍効果が変化することが報告されているが、腫瘍溶解性ウイルスの抗腫瘍効果が変化するかは不明であった。今回の研究結果から抗生剤処理により腫瘍溶解性ウイルスの抗腫瘍効果が変化することを見出し、その抗腫瘍効果の変化に腸内細菌叢が関与する結果を得た。

Research Products

• [Journal Article] Oncolytic herpes simplex virus HF10 (canerpaturev, C-REV) promotes accumulation of CD8+PD-1- tumor-infiltrating T cells in PD-L1 enriched tumor microenvironment. (2021)
  • Author(s): Eissa I.R., Mukoyama N., Abdelmoneim, M., Naoe, Y., Matsumura, S., Bustos-Villalobos I., Ichinose T., Miyajima N., Morimoto D., Tanaka M., Fujimoto, Y., Kodera Y., Kasuya H.
  • Journal Title: Int. J. Cancer Volume: 1 Issue: 1 Pages: 1-14
  • DOI: 10.1002/ijc.33550
  • Peer Reviewed
• [Journal Article] Combination of Cetuximab and Oncolytic Virus Canerpaturev Synergistically Inhibits Human Colorectal Cancer Growth (2019)
  • Author(s): Wu Zhiwen、Ichinose Toru、Naoe Yoshinori、Matsumura Shigeru、Villalobos Itzel Bustos、Eissa Ibrahim Ragab、Yamada Suguru、Miyajima Noriyuki、Morimoto Daishi、Mukoyama Nobuaki、Nishikawa Yoko、Koide Yusuke、Kodera Yasuhiro、Tanaka Maki、Kasuya Hideki
  • Journal Title: Molecular Therapy - Oncolytics Volume: 13 Pages: 107-115
  • DOI: 10.1016/j.omto.2019.04.004
  • Peer Reviewed / Open Access
• [Presentation] 腫瘍溶解性ウイルスC-REV(HF10)に関連する抗腫瘍因子の検討 (2019)
  • Author(s): Hideki Kasuya, Daishi Morimoto, Yoshinori Naoe, Shigeru Matsumura, Itzel Bustos, Ibrahim Eissa, Maki Tanaka
  • Organizer: 第21回外科分子細胞治療研究会
• [Presentation] 腫瘍溶解性ウイルスC-REV(旧 HF10)による膵癌延命治療の可能性 (2019)
  • Author(s): Hideki Kasuya, Yoshiki Hirooka, Maki Tanaka
  • Organizer: 第105回日本消化器病学会総会
• [Presentation] 腫瘍溶解性ウイルスC-REVの膵臓癌に対する効果関連因子の探索 (2019)
  • Author(s): Hideki Kasuya, Yoshiki Hirooka, Yoshinori Naoe, Shigeru Matsumura, Daishi Morimoto, Ibrahim Eissa, Maki Tanaka
  • Organizer: 第50回日本膵臓学会大会
• [Presentation] PD-L1 Blockade Enhanced the Therapeutic Efficacy of the Oncolytic Virus-Canerpaturev in Squamous Carcinoma (2019)
  • Author(s): Ibrahim Eissa, Nobuaki Mukoyama, Yoshinori Naoe, Shigeru Matsumura, Toru Ichinose, Itzel Bustos, Daishi Morimoto, Noriyuki Miyajima, Maki Tanaka, Hideki Kasuya
  • Organizer: 第25回日本遺伝子細胞治療学会学術集会
• [Presentation] Combination therapy of Cetuximab and CANERPATUREV suppresses human colorectal cancer growth (2019)
  • Author(s): Shigeru Matsumura, Zhiwen Wu, Toru Ichinose, Yoshinori Naoe, Itzel Bustos, Ibrahim Eissa, Suguru Yamada, Noriyuki Miyajima, Daishi Morimoto Nobuaki Mukoyama Yoko Nishikawa, Yusuke Koide, Yasuhiro Kodera, Maki Tanaka, Hideki Kasuya
  • Organizer: 第25回日本遺伝子細胞治療学会学術集会
• [Presentation] Antitumor factors associated with oncolytic virus C-REV(formaly HF10) (2019)
  • Author(s): Hideki Kasuya, Yoshiki Hirooka, Masaya Suenaga, Daishi Morimoto, Yoshinori Naoe, Shigeru Matsumura, Maki Tanaka
  • Organizer: The 17th IDDST conference
  • Int'l Joint Research / Invited
• [Presentation] PD-L1 Blockade Enhanced the Therapeutic Efficacy of Oncolytic Virus Canerpaturev in Squamous Cell Carcinoma Model (2019)
  • Author(s): Ibrahim Eissa, Nobuaki Mukoyama, Yoshinori Naoe, Shigeru Matsumura, Toru Ichinose, Itzel Bustos, Daishi Morimoto, Noriyuki Miyajima, Maki Tanaka, Hideki Kasuya
  • Organizer: 第23回日本がん免疫学会総会
• [Presentation] Combination of Cetuximab and oncolytic virus CANERPATUREV synergistically inhibits human colorectal cancer growth (2019)
  • Author(s): Shigeru Matsumura, Zhiwen Wu, Toru Ichinose, Yoshinori Naoe, Itzel Bustos, Ibrahim Eissa, Suguru Yamada, Yasuhiro Kodera, Maki Tanaka, Hideki Kasuya
  • Organizer: 第23回日本がん免疫学会総会
• [Presentation] Combination of Cetuximab and oncolytic virus CANERPATUREV synergistically inhibits human colorectal cancer growth (2019)
  • Author(s): Shigeru Matsumura, Zhiwen Wu, Toru Ichinose, Ibrahim Eissa, Yoshinori Naoe, Yasuhiro Kodera, Maki Tanaka, Hideki Kasuya
  • Organizer: 第78回日本癌学会学術総会
• [Presentation] Clinical development of Canerpaturev(formerly HF10)as the novel cancer therapy (2019)
  • Author(s): Hideki Kasuya, Yoshinori Naoe, Shigeru Matsumura, Maki Tanaka
  • Organizer: The 12th International Oncolytic Virotherapy Conference
  • Int'l Joint Research
• [Remarks] 名古屋大学大学院医学系研究科 癌免疫治療研究室
  • URL: https://www.med.nagoya-u.ac.jp/intlexch/cancerimmuno/www/index.html