Tumor-targeted MAPK-dependent recombinant vaccinia virus for oncolytic virotherapy

• Project/Area Number: 15H04310
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Tumor therapeutics
• Research Institution: Tottori University
• Principal Investigator: NAKAMURA Takafumi 鳥取大学, 医学(系)研究科(研究院), 准教授 (70432911)
• Research Collaborator: HASEGAWA kosei
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥16,900,000 (Direct Cost: ¥13,000,000、Indirect Cost: ¥3,900,000); Fiscal Year 2017: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2016: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000); Fiscal Year 2015: ¥7,280,000 (Direct Cost: ¥5,600,000、Indirect Cost: ¥1,680,000)
• Keywords: 腫瘍治療学 / 遺伝子治療 / バイオマーカー / 免疫活性化 / 癌 / ウイルス療法 / トランスレーショナルリサーチ / バイオテクノロジー

Outline of Final Research Achievements

In clinically relevant mouse models of liver metastasis of human pancreatic cancer cells, single intravenous injection of MAPK-Dependent Recombinant Vaccinia Virus (MDRVV) significantly prolonged survival following tumor-specific viral replication and oncolysis. Furthermore, the MAPK-dependent tumor-specific replication of MDRVV was confirmed in ex vivo infection of live tissues from six pancreatic cancer patients. On the other hand, UCA1 promotes cell-to-cell spread of MDRVV in ovarian cancer, showing the possibility of applying UCA1 expression as a predictivebiomarker to predict the therapeutic effect of MDRVV.

Academic Significance and Societal Importance of the Research Achievements

現行の治療法に対して極めて高い抵抗性を示し、容易に他臓器に転移する難治性進行癌に対する新規治療法の確立が望まれている。学術的意義は、癌特異的に増殖し破壊する遺伝子組換えワクシニアウイルス（MDRVV）が実際の臨床像を反映したマウスモデルにおいても高い抗癌効果を発揮することを実証する、MDRVVの抗癌効果を予測するためのバイオマーカーを同定する、さらに癌免疫療法との併用による抗癌効果の最適化を達成することにある。社会的意義は、現行の治療法に極めて高い抵抗性を示す難治性悪性腫瘍に対するMDRVVによる革新的なウイルス療法の確立に直結することにある。

Research Products

• [Journal Article] lncRNA UCA1-Mediated Cdc42 Signaling Promotes Oncolytic Vaccinia Virus Cell-to-Cell Spread in Ovarian Cancer (2019)
  • Author(s): Horita Kosuke、Kurosaki Hajime、Nakatake Motomu、Kuwano Nozomi、Oishi Tetsuro、Itamochi Hiroaki、Sato Sho、Kono Hiromichi、Ito Mai、Hasegawa Kosei、Harada Tasuku、Nakamura Takafumi
  • Journal Title: Molecular Therapy - Oncolytics Volume: 13 Pages: 35-48
  • DOI: 10.1016/j.omto.2019.03.003
  • Peer Reviewed / Open Access
• [Journal Article] Efficacy and Safety of Doubly-Regulated Vaccinia Virus in a Mouse Xenograft Model of Multiple Myeloma (2017)
  • Author(s): Muneyoshi Futami, Kota Sato, Kanji Miyazaki, Kenshi Suzuki, Takafumi Nakamura and Arinobu Tojo
  • Journal Title: Molecular Therapy Oncolytics Volume: 6 Pages: 57-68
  • DOI: 10.1016/j.omto.2017.07.001
  • Peer Reviewed / Open Access
• [Journal Article] 腫瘍特異的に増殖する遺伝子組換えワクシニアウイルス (2016)
  • Author(s): 中村 貴史
  • Journal Title: 実験医学 Volume: 34 Pages: 31-37
• [Presentation] がんのみを標的破壊するワクシニアウイルスベクターの開発 (2018)
  • Author(s): 中村 貴史
  • Organizer: 日本薬学会 第138年
  • Invited
• [Presentation] Novel Approach for Systemic Cancer Therapy with Oncolytic Vaccinia Virus through Evading the Host Immune Response (2018)
  • Author(s): Nakatake M, Kurosaki H, Nakamura T
  • Organizer: 21th Annual Meeting of American Society of Gene & Cell Therapy
  • Int'l Joint Research
• [Presentation] Predictive biomarkers for cancer virotherapy with oncolytic vaccinia virus (2018)
  • Author(s): Horita K, Kurosaki H, Nakatake M, Kuwano N, Ishii K, Kohno H, Ito M, Itamochi H, Oishi T, Harada T, Nakamura T
  • Organizer: 第24回日本遺伝子細胞治療学会
• [Presentation] Preclinical toxicological evaluation of tumor-targeted and armed oncolytic vaccinia virus in cynomolgus monkey (2018)
  • Author(s): Kurosaki H, Okamura T, Ito M, Nakatake M, Kuwano N, Horita K, Ishii K, Kohno H, Yasutomi Y, Nakamura T
  • Organizer: 第24回日本遺伝子細胞治療学会
• [Presentation] Novel approach for systemic cancer therapy with oncolytic vaccinia virus through evading the host immune response (2018)
  • Author(s): Nakatake M, Kurosaki H, Nakamura T
  • Organizer: 第24回日本遺伝子細胞治療学会
• [Presentation] 腫瘍溶解性ウイルスによるがんウイルス療法の現状と展望 (2018)
  • Author(s): 中村 貴史
  • Organizer: 第3回日本遺伝子細胞学会若手研究会セミナー
• [Presentation] Tumor-targeted and armed oncolytic vaccinia virus for systemic cancer virotherapy (2017)
  • Author(s): Nakamura T
  • Organizer: 第23回日本遺伝子細胞治療学会
  • Invited
• [Presentation] 難治性がんを標的破壊する武装化遺伝子組換えワクシニアウイルスによる全身性がんウイルス療法の開発 (2017)
  • Author(s): 中村 貴史
  • Organizer: 第76回日本癌学会学術総会
  • Invited
• [Presentation] 分子生物学的アプローチを駆使してウイルスを知り、そしてがん治療に利用する (2017)
  • Author(s): 中村 貴史
  • Organizer: 第40回日本分子生物学会年
  • Invited
• [Presentation] Preclinical Study of Tumor-targeted and Armed Oncolytic Vaccinia Virus for Systemic Cancer Virotherapy (2017)
  • Author(s): Nakatake M, Kurosaki H, Horita K, Kuwano N, Ishii K, Nomura M, Sakamoto T, Okamura T, Yasutomi Y, Nakamura T
  • Organizer: 20th Annual Meeting of American Society of Gene & Cell Therapy
  • Int'l Joint Research
• [Presentation] Preclinical toxicological evaluation of tumor-targeted and armed oncolytic vaccinia virus in cynomolgus monkey (2017)
  • Author(s): Kurosaki H, Okamura T, Nakatake M, Kuwano N, Horita K, Ishii K, Yasutomi Y, Nakamura T
  • Organizer: 第23回日本遺伝子細胞治療学会
• [Presentation] Tumor-targeting and CD/UPRT-armed oncolytic vaccinia virus enhanced their therapeutic efficacy by combination with prodrug 5-FC (2017)
  • Author(s): Nakatake M, Kuwano N, Horita K, Ishii K, Sakamoto T, Kurosaki H, Nakamura T
  • Organizer: 第23回日本遺伝子細胞治療学会
• [Presentation] IncRNA UCA1 has the potential to be a biomarker of therapeutic response to oncolytic vaccinia virus in paclitaxel resistant ovarian cancer (2017)
  • Author(s): Horita K, Kurosaki H, Nakatake M, Kuwano N, Ishii K, Itamochi H, Oishi T, Harada T, Nakamura T
  • Organizer: 第23回日本遺伝子細胞治療学会
• [Presentation] 難治性がんを標的破壊する遺伝子組換えワクシニアウイルスによるがんウイルス療法の開発 (2017)
  • Author(s): 中村 貴史
  • Organizer: 第2回日本遺伝子細胞学会若手研究会セミナー
• [Presentation] Preclinical study for tumor-targeted and armed oncolytic vaccinia virus for systemic cancer virotherapy (2016)
  • Author(s): Nakamura T, Nakatake M, Horita K, Ishii K, kuwano N, Nomura M and Kurosaki H
  • Organizer: 10th International Conference on Oncolytic Viruses As Cancer Therapeutics
  • Place of Presentation: Fairmont Waterfront Hotel (Vancouver, Canada)
  • Year and Date: 2016-10-03
  • Int'l Joint Research
• [Presentation] Upregulated lncRNA-UCA1 enhances therapeutic effect of oncolytic vaccinia virus in paclitaxel-resistant human malignant tumors (2016)
  • Author(s): Nakamura T, Horita K, Nakatake M, kuwano N, Ishii K, Nomura M and Kurosaki H
  • Organizer: 10th International Conference on Oncolytic Viruses As Cancer Therapeutics
  • Place of Presentation: Fairmont Waterfront Hotel (Vancouver, Canada)
  • Year and Date: 2016-10-02
  • Int'l Joint Research
• [Presentation] Upregulated lncRNA-UCA1 enhances therapeutic effect of oncolytic vaccinia virus in paclitaxel resistant ovarian cancer (2016)
  • Author(s): Horita K, Kurosaki H, Nakatake M, kuwano N, Ishii K, Parada R, Nomura M, Itamochi H, Oishi T, Harada T and Nakamura T
  • Organizer: 第22回日本遺伝子細胞治療学会
  • Place of Presentation: 東京慈恵会医科大学（東京都）
  • Year and Date: 2016-07-29
• [Presentation] Preclinical study for tumor-targeted and armed oncolytic vaccinia virus for systemic cancer virotherapy (2016)
  • Author(s): Nakatake M, Kurosaki H, Yamane M, Horita K, Ishii K, kuwano N, Hasegawa K, Fujiwara K, Nomura M, Parada R and Nakamura T
  • Organizer: 第22回日本遺伝子細胞治療学会
  • Place of Presentation: 東京慈恵会医科大学（東京都）
  • Year and Date: 2016-07-29
• [Presentation] 難治性がんを標的破壊する遺伝子組換えワクシニアウイルスによる全身性がんウイルス療法の開発 (2015)
  • Author(s): 中村 貴史
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: 名古屋国際会議場（名古屋市）
  • Year and Date: 2015-10-09
• [Presentation] Enhancing tumor specificity and therapeutic index of oncolytic vaccinia virus through deletions of both VGF and O1 protein genes (2015)
  • Author(s): Nakatake M, Yamane M, Parada R, Horita K, Okazaki M, Hasegawa K, Miyara A, Fujiwara K, Kurosaki H, Nakamura T
  • Organizer: The 21st Annual Meeting of Japan Society of Gene Therapy
  • Place of Presentation: 大阪国際会議場（大阪市）
  • Year and Date: 2015-07-25
• [Presentation] Identification of host factors required for enhancing replication and spread of oncolytic vaccinia virus (2015)
  • Author(s): Horita K, Nakatake M, Goto I, Yamane M, Okazaki M, Parada R, Kurosaki H, Nakamura T
  • Organizer: The 21st Annual Meeting of Japan Society of Gene Therapy
  • Place of Presentation: 大阪国際会議場（大阪市）
  • Year and Date: 2015-07-25
• [Presentation] Tumor-specific, replication-competent vaccinia virus for systemic oncolytic virotherapy (2015)
  • Author(s): Nakamura T
  • Organizer: The 21st Annual Meeting of Japan Society of Gene Therapy
  • Place of Presentation: 大阪国際会議場（大阪市）
  • Year and Date: 2015-07-24
• [Presentation] Deletions of both vaccinia growth factor and O1 protein genes enhance therapeutic index of oncolytic vaccinia virus (2015)
  • Author(s): Nakatake M, Yamane M, Horita K, Okazaki M, Roxana Parada R, Hajime Kurosaki H, Nakamura T
  • Organizer: 9th International Conference on Oncolytic Viruses As Cancer Therapeutics
  • Place of Presentation: Boston Park Plaza Hotel（Boston, USA）
  • Year and Date: 2015-06-15
  • Int'l Joint Research
• [Presentation] 純和製ワクシニアウイルスを用いた難治がんに対するウイルス療法の開発 (2015)
  • Author(s): 中村 貴史
  • Organizer: 第23回遺伝子治療推進産学懇話会
  • Place of Presentation: 京都大学東京オフィス（東京都）
  • Year and Date: 2015-04-10
  • Invited
• [Book] 遺伝子治療の新局面 (2019)
  • Author(s): 中村貴史
  • Total Pages: 7
  • Publisher: 医歯薬出版株式会社
  • ISBN: 4910204770394
• [Book] 先端治療技術の実用化と開発戦略 (2017)
  • Author(s): 中村貴史
  • Total Pages: 8
  • Publisher: 技術情報協会
  • ISBN: 9784861047473
• [Book] 次世代がん治療 : 発症・転移メカニズムからがん免疫療法・ウイルス療法、診断法まで (2017)
  • Author(s): 中村貴史
  • Total Pages: 7
  • Publisher: エヌ・ティー・エス
  • ISBN: 9784860435035
• [Book] ワクシニアウイルス（遺伝子医学 MOOK30号） (2016)
  • Author(s): 中村貴史
  • Publisher: 株式会社メディカルドゥ
• [Remarks] 研究内容紹介
  • URL: http://www.med.tottori-u.ac.jp/integbio/522/1198.html
• [Remarks] がんナビ
  • URL: http://medical.nikkeibp.co.jp/leaf/all/cancernavi/report/201301/528660_3.html
• [Remarks] ウイルスで新しいがん療法の開発をめざす
  • URL: http://ganshien.umin.jp/research/main/nakamura/index.html
• [Patent(Industrial Property Rights)] 外来遺伝子発現ワクシニアウイルスの製造方法 (2017)
  • Inventor(s): 中村貴史、中武大夢、黒﨑創、堀田享佑
  • Industrial Property Rights Holder: 鳥取大学
  • Industrial Property Rights Type: 特許
  • Filing Date: 2017
  • Overseas
• [Patent(Industrial Property Rights)] ワクシニアウイルスの増殖・伝搬を増強する宿主制御因子 (2016)
  • Inventor(s): 中村貴史、堀田享佑、黒崎 創、中武大夢
  • Industrial Property Rights Holder: 鳥取大学
  • Industrial Property Rights Type: 特許
  • Filing Date: 2016-07-22
  • Overseas
• [Patent(Industrial Property Rights)] ワクシニアウイルスの増殖・伝搬を増強する宿主制御因子 (2015)
  • Inventor(s): 中村 貴史、堀田 享佑、黒﨑 創、中武 大夢
  • Industrial Property Rights Holder: 鳥取大学
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2015-145153
  • Filing Date: 2015-07-22