増殖型単純ヘルペスウイルスを利用したがんウイルス療法の開発

• Project/Area Number: 18015022
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Nagoya University
• Principal Investigator: 西山 幸廣 Nagoya University, 大学院・医学系研究科, 教授 (60115615)
• Project Period (FY): 2006 – 2007
• Project Status: Completed (Fiscal Year 2007)
• Budget Amount: ¥9,400,000 (Direct Cost: ¥9,400,000); Fiscal Year 2007: ¥4,700,000 (Direct Cost: ¥4,700,000); Fiscal Year 2006: ¥4,700,000 (Direct Cost: ¥4,700,000)
• Keywords: 単純ヘルペスウイルス / ウイルス療法 / がん治療 / サイトカイン / アンプリコン

Research Abstract

我々はがんの治療を目的として、増殖型、弱毒化単純ヘルペスウイルス(HSV)の有効性、安全性を動物実験系で評価し、変異HSV-1HF10が優れた抗腫瘍性をもつことを報告してきた。また、再発性乳癌、頭頸部癌を対象にトランスレーショナルリサーチを行い、HF10が高い腫瘍細胞溶解性をもつことを示してきた。
本研究ではHF10のマウス悪性黒色腫モデルに対する全身性免疫誘導能について検討を行った。
DNA/2マウスの腹腔内にclone M3を接種した腹腔内腫瘍モデルでは、腫瘍形成後にHF10を腹腔内接種すると全例が生存する。その後マウス皮下に腫瘍細胞を再接種し、腫瘍形成の有無を経時的に観察した。その結果、マウスの治療後腫瘍細胞を再接種しても6匹中5匹で皮下腫瘍は形成されないことが判明した。また、マウスの両側背部に腫瘍細胞を接種し、片側のみにHF10を感染させ、感染側、非感染側の腫瘍の増大についても観察した。その結果、ウイルス接種をしていない側の腫瘍の増大も有意に抑制されることがわかった。さらに、皮下腫瘍モデル系で治療したマウスから摘出した脾臓を用い、皮下腫瘍モデルマウスに移入免疫し、腫瘍増大抑制効果について検討した。その結果、皮下腫瘍及び腹腔内腫瘍のモデルで腫瘍増大の抑制が認められることが判明した。
以上の結果から、HF10の腫瘍内投与による悪性黒色腫の治療により全身的な抗腫瘍免疫が誘導されている可能性が示された。

Research Products

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• [Journal Article] Oncolytic Virotherapy with an HSV amplicon vector expressing granulocyte-macrophage colony-stimulating factor using the replication-competent HSV type Imutant HF10 as a helper (2007)
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• [Journal Article] Suitability of a US3-inactivated HSV mutant (LIBRI) as an oncolytic-virus for pancreatic cancer therpay. (2007)
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• [Journal Article] Determination and analysis of the DNA sequence of highly attenuated herpes simplex virus type 1 mutant HF10, a potential oncolytic virus. (2007)
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• [Journal Article] Beneficial Effect of GB Virus C Co-Infection in Human Immunodeficiency Virus Type 1-Infected Individuals. (2007)
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• [Journal Article] Replication-competent herpes simplex virus : a novel and promising modality for cancer therapy. (2007)
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  • Journal Title: Current Topics in Virology (in press)
• [Journal Article] Intercellular trafficking and cytotoxicity of recombinant HSV-1 thymidine kinase fused with HSV-2 US11 RXP repeat peptide. (2007)
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  • Journal Title: Virus Genes (in press)
• [Journal Article] Simultaneous quantification of Epstein-Barr virus, Cytomegalovirus, and human Herpesvirus 6 DNA in transplant recipients by multiplex real-time PCR assay. (2007)
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  • Journal Title: Journal of Clinical Microbiology (in press)
• [Journal Article] Enhanced efficacy of herpes simplex virus mutant HF10 combined with paclitaxel in peritoneal cancer dissemination models. (2007)
  • Author(s): Shimoyama, S., Goshima, F., Teshigahara, O., et al.
  • Journal Title: Hepato-Gastroenterology (in press)
• [Journal Article] Suitability of a US3-inactivated HSV mutant(L1BR1) as an oncolytic-virus for pancreatic cancer therpay. (2007)
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  • Journal Title: Cancer Gene Therapy (in press)
• [Journal Article] Association of two membrane proteins encoded by herpes simplex virus type2, UL11 and UL56. (2006)
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• [Journal Article] Latent infection of human herpesvirus 7 in CD4(+)T lymphocytes. (2006)
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• [Journal Article] Herpes simplex virus US3 protein kinase regulates virus-induced apoptosis in olfactory and vomeronasal chemosensory neurons in vivo. (2006)
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• [Journal Article] Intratumoral injection of herpes simplex virus HF10 in recurrent head and neck squamous cell carcinoma. (2006)
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• [Journal Article] Accessory genes define the relationship between the herpes simplex virus and its host. (2006)
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• [Journal Article] Pilot study of oncolytic viral therapy using mutant herpes simplex virus HF10 against recurrent metastatic breast cancer. (2006)
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• [Journal Article] Rapid detection of Epstein-Barr virus DNA by loop-mediated isothermal amplification method. (2006)
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• [Journal Article] Establishment of a novel foreign gene delivery system combining an HSV amplicon with an attenuated replication-competent virus, HSV-1 HF10. (2006)
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