Augmentation of tumor specificity and killing activity of oncolytic herpes virus vectors

• Project/Area Number: 25290059
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Tumor therapeutics
• Research Institution: The University of Tokyo (2014-2015); Tokyo University of Pharmacy and Life Science (2013)
• Principal Investigator: Uchida Hiroaki 東京大学, 医科学研究所, 講師 (20401250)
• Co-Investigator(Kenkyū-buntansha): YAMAGUCHI MIKI 札幌医科大学, 医学部, 助教 (10530454) ; FUKUHARA TAKESHI 東京薬科大学, 生命科学部, 助教 (20359673) ; TAHARA HIDEAKI 東京大学, 医科学研究所, 教授 (70322071)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥17,030,000 (Direct Cost: ¥13,100,000、Indirect Cost: ¥3,930,000); Fiscal Year 2015: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2014: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000); Fiscal Year 2013: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000)
• Keywords: 遺伝子治療 / 腫瘍溶解性ウイルス療法 / ヘルペスウイルス / 抗体 / がん / 腫瘍溶解ウイルス療法

Outline of Final Research Achievements

We previously reported a retargeted herpes simplex virus (HSV) platform that incorporates single-chain antibodies (scFv) into gD to mediate entry solely via cancer antigens. In this study, we introduced syncytial mutations, known to confer hyperactivity in cell-cell fusion, into our retargeted HSVs, and found that the mutations enabled extensive formation of syncytia and enhanced killing activity on human tumor lines that express the target molecules. Furthermore, we took advantage of our collection of monoclonal antibodies selected for targeting activity as components of gene delivery vectors. We derived an scFv from a hybridoma clone that produces an anti-epithelial cell adhesion molecule (EpCAM) antibody, and inserted it into our retargeted platform, and found that the virus showed EpCAM-dependent virus entry and spread. Our strategies may be useful to develop a widely applicable oncolytic HSV platform that confers powerful oncolytic activity and stringent tumor selectivity.

Research Products

• [Int'l Joint Research] University of Pittsburgh(米国)
• [Journal Article] Development of an oncolytic HSV vector fully retargeted specifically to cellular EpCAM for virus entry and cell-to-cell spread. (2016)
  • Author(s): Shibata T, Uchida H, Shiroyama T, Okubo Y, Suzuki T, Ikeda H, Yamaguchi M, Miyagawa Y, Fukuhara T, Cohen JB, Glorioso JC, Watabe T, Hamada H, Tahara H.
  • Journal Title: Gene Therapy. Volume: 印刷中 Issue: 6 Pages: 479-488
  • DOI: 10.1038/gt.2016.17
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] A newly developed anti-Mucin 13 monoclonal antibody targets pancreatic ductal adenocarcinoma cells. (2015)
  • Author(s): Nishii Y, Yamaguchi M, Kimura Y, Hasegawa T, Aburatani H, Uchida H, Hirata K, Sakuma Y.
  • Journal Title: International Journal of Oncology. Volume: 46 Issue: 4 Pages: 1781-1787
  • DOI: 10.3892/ijo.2015.2880
  • Peer Reviewed
• [Journal Article] 大腸癌の遺伝子治療・ウイルス療法 (2015)
  • Author(s): 内田宏昭, 田原秀晃
  • Journal Title: 日本臨床 Volume: 1077 Pages: 569-573
• [Journal Article] Herpes simplex viral-vector design for efficient transduction of nonneuronal cells without cytotoxicity. (2015)
  • Author(s): Miyagawa Y, Marino P, Verlengia G, Uchida H, Goins WF, Yokota S, Geller DA, Yoshida O, Mester J, Cohen JB, Glorioso JC.
  • Journal Title: Proceedings of the National Academy of Sciences of the United States of America. Volume: 112 Issue: 13
  • DOI: 10.1073/pnas.1423556112
  • Peer Reviewed
• [Journal Article] Use of miRNA response sequences to block off-target replication and increase the safety of an unattenuated, glioblastoma-targeted oncolytic HSV. (2015)
  • Author(s): Mazzacurati L, Marzulli M, Reinhart B, Miyagawa Y, Uchida H, Goins WF, Li A, Kaur B, Caligiuri M, Cripe T, Chiocca N, Amankulor N, Cohen JB, Glorioso JC, Grandi P.
  • Journal Title: Molecular Therapy. Volume: 23 Issue: 1 Pages: 99-107
  • DOI: 10.1038/mt.2014.177
  • Peer Reviewed
• [Journal Article] Development of a sensitive screening method for selecting monoclonal antibodies to be internalized by cells. (2014)
  • Author(s): Yamaguchi M, Nishii Y, Nakamura K, Aoki H, Hirai S, Uchida H, Sakuma Y, Hamada H.
  • Journal Title: Biochemical and Biophysical Research Communications. Volume: 454 Issue: 4 Pages: 600-603
  • DOI: 10.1016/j.bbrc.2014.10.133
  • Peer Reviewed
• [Journal Article] A targeting ligand enhances infectivity and cytotoxicity of an oncolytic adenovirus in human pancreatic cancer tissues. (2014)
  • Author(s): Yamamoto Y, Hiraoka N, Goto N, Rin Y, Miura K, Narumi K, Uchida H, Tagawa M, Aoki K.
  • Journal Title: Journal of Control Release. Volume: 192 Pages: 284-293
  • DOI: 10.1016/j.jconrel.2014.07.053
  • Peer Reviewed
• [Journal Article] Development of a novel efficient method to construct an adenovirus library displaying random peptides on the fiber knob. (2014)
  • Author(s): Yamamoto Y, Goto N, Miura K, Narumi K, Ohnami S, Uchida H, Miura Y, Yamamoto M, Aoki K.
  • Journal Title: Molecular Pharmaceutics Volume: -
  • Peer Reviewed
• [Journal Article] Expression of HSV-1 receptors in EBV-associated lymphoproliferative disease determines susceptibility to oncolytic HSV. (2013)
  • Author(s): Wang PY, Currier MA, Hansford L, Kaplan D, Chiocca EA, Uchida H, Goins WF, Cohen JB, Glorioso JC, Kuppevelt TH, Mo X, Cripe TP.
  • Journal Title: Gene Therapy Volume: 20 Issue: 7 Pages: 761-769
  • DOI: 10.1038/gt.2012.93
  • Peer Reviewed
• [Journal Article] Effective treatment of an orthotopic xenograft model of human glioblastoma using an EGFR-retargeted oncolytic herpes simplex virus. (2013)
  • Author(s): Uchida H, Marzulli M, Nakano K, Goins WF, Chan J, Hong CS, Mazzacurati L, Yoo JY, Haseley A, Nakashima H, Baek H, Kwon H, Kumagai I, Kuroki M, Kaur B, Chiocca EA, Grandi P, Cohen JB, Glorioso JC.
  • Journal Title: Molecular Therapy Volume: 21 Issue: 3 Pages: 561-569
  • DOI: 10.1038/mt.2012.211
  • Peer Reviewed
• [Journal Article] Novel mutations in gB and gH circumvent the requirement for known gD receptors in HSV-1 entry and cell-to-cell spread. (2013)
  • Author(s): Uchida H, Chan J, Shrivastava I, Reinhart B, Grandi P, Glorioso JC, Cohen JB.
  • Journal Title: Journal of Virology Volume: 87 Issue: 3 Pages: 1430-1442
  • DOI: 10.1128/jvi.02804-12
  • Peer Reviewed
• [Presentation] がん細胞のみに侵入可能な標的化改変ヘルペスウイルスの開発 (2016)
  • Author(s): 内田宏昭
  • Organizer: 第116回日本外科学会定期学術集会
  • Place of Presentation: 大阪国際会議場（大阪府大阪市）
  • Year and Date: 2016-04-14
• [Presentation] 腫瘍細胞表面抗原を介して侵入する標的化単純ヘルペスウイルスベクターの開発 (2015)
  • Author(s): 城山智貴, 内田宏昭, 大久保優, 柴田智子, 福原武志, 山口美樹, Justus B. Cohen, Joseph C. Glorioso, 渡部徹郎, 濱田洋文, 田原秀晃
  • Organizer: 第7回血液疾患免疫療法研究会
  • Place of Presentation: 東京大学本郷キャンパス（東京都文京区）
  • Year and Date: 2015-09-26
• [Presentation] Exploration of cancer-targeting antibodies using an HSV-based screening system for development of novel HSV vectors fully retargeted to cancer cells. (2015)
  • Author(s): 内田宏昭
  • Organizer: The 21th Annual Meeting of Japan Society of Gene Therapy.
  • Place of Presentation: 大阪国際会議場（大阪府大阪市）
  • Year and Date: 2015-07-24
• [Presentation] がん細胞表面抗原を介して細胞内侵入する標的化改変単純ヘルペスウイルスベクターの開発 (2015)
  • Author(s): 内田宏昭
  • Organizer: 第56回日本臨床ウイルス学会
  • Place of Presentation: 岡山大学鹿田キャンパス（岡山県岡山市）
  • Year and Date: 2015-06-13
  • Invited
• [Presentation] Development of a new generation of herpes simplex virus vectors fully retargeted to a variety of tumor-associated antigens. (2014)
  • Author(s): Uchida H, Okubo Y, Shibata T, Suzuki T, Ikeda H, Shiroyama T, Fukuhara T, Kojima M, Yamaguchi M, Miyagawa Y, Cohen JB, Glorioso JC, Hamada H.
  • Organizer: The 20th Annual Meeting of Japan Society of Gene Therapy.
  • Place of Presentation: 東京慈恵会医科大学（東京都港区）
  • Year and Date: 2014-08-06 – 2014-08-08
• [Presentation] Exploration of cancer-targeting antibodies using an HSV-based screening system. (2014)
  • Author(s): Okubo Y, Ikeda H, Fukuhara T, Kojima M, Cohen JB, Glorioso JC, Hamada H, Watabe T, Uchida H.
  • Organizer: The 39th International Herpesvirus Workshop.
  • Place of Presentation: 神戸コンベンションセンター（兵庫県神戸市）
  • Year and Date: 2014-07-19 – 2014-07-23
• [Presentation] Generation of an EpCAM-retargeted HSV vector by application of in-house monoclonal antibody resources. (2014)
  • Author(s): Shibata T, Shiroyama T, Suzuki T, Okubo Y, Fukuhara T, Yamaguchi M, Miyagawa Y, Cohen JB, Glorioso JC, Hamada H, Watabe T, Uchida H.
  • Organizer: The 39th International Herpesvirus Workshop.
  • Place of Presentation: 神戸コンベンションセンター（兵庫県神戸市）
  • Year and Date: 2014-07-19 – 2014-07-23
• [Presentation] Augmentation of oncolytic potential of a fully retargeted HSV vector by introduction of syncytial mutations. (2014)
  • Author(s): Wakata A, Okubo Y, Fukuhara T, Cohen JB, Glorioso JC, Nakano K, Kumagai I, Kuroki M, Hamada H, Watabe T, Uchida H.
  • Organizer: The 39th International Herpesvirus Workshop.
  • Place of Presentation: 神戸コンベンションセンター（兵庫県神戸市）
  • Year and Date: 2014-07-19 – 2014-07-23
• [Presentation] 単純ヘルペスウイルスの標的化改変プラットフォームへのがん標的化抗体インハウスリソースの適用 (2013)
  • Author(s): 柴田智子, 鈴木拓真, 大久保優, 駒井麻央, 福原武志, 山口美樹, 平井幸恵, 宮川世志幸, Justus Cohen, Joseph Glorioso, 濱田洋文, 内田宏昭
  • Organizer: 第61回日本ウイルス学会学術集会
  • Place of Presentation: 神戸
• [Presentation] エンベロープ糖タンパクgDにがん標的化単鎖抗体を挿入した単純ヘルペスウイルスを用いた腫瘍溶解ウイルス療法の開発 (2013)
  • Author(s): 鈴木拓真, 柴田智子, 大久保優, 福原武志, 宮川世志幸, Justus Cohen, Joseph Glorioso, 中野賢二, 熊谷泉, 黒木政秀, 山口美樹, 平井幸恵, 濱田洋文, 内田宏昭
  • Organizer: 第61回日本ウイルス学会学術集会
  • Place of Presentation: 神戸
• [Presentation] Manipulation of multiple herpes simplex virus glycoproteins for fully retargeted entry and efficient cell-to-cell spread. (2013)
  • Author(s): Wakata A, Okubo Y, Fukuhara T, Cohen JB, Glorioso JC, Nakano K, Kumagai I, Kuroki M, Hamada H, Uchida H.
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: 横浜
• [Presentation] Application of in-house monoclonal antibody resources to a fully retargeted oncolytic herpes simplex virus platform. (2013)
  • Author(s): Okubo Y, Suzuki T, Shibata T, Komai M, Fukuhara T, Yamaguchi M, Hirai S, Miyagawa Y, Cohen JB, Glorioso JC, Hamada H, Uchida H.
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: 横浜
• [Presentation] Syncytial mutations augment the oncolytic potential of a fully retargeted herpes simplex virus vector. (2013)
  • Author(s): Wakata A, Okubo Y, Fukuhara T, Cohen JB, Joseph C. Glorioso JC, Nakano K, Kumagai I, Kuroki M, Hamada H, Uchida H.
  • Organizer: The 19th Annual Meeting of Japan Society of Gene Therapy.
  • Place of Presentation: 岡山
• [Remarks] 東京大学医科学研究所先端医療研究センター臓器細胞工学分野ホームページ
  • URL: http://www.ims.u-tokyo.ac.jp/sur+trans/sur+be/index.html