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JCI:天花疫苗瞄准癌症

来源:生物谷 2007-11-02 09:22

  科学家发现,在天花的根除中起到重要作用的一种病毒在癌症治疗中也能够大显身手。在一项新研究中,一个转基因牛痘株,即人们所说的天花疫苗,能够抑制兔子肝脏肿瘤的生长。如今,这种病毒正在向着进行人体临床试验的目标迈进。

  10多年来,科学家一直试图用经过遗传手段改良的病毒传染并破坏癌细胞,但只获得了有限的成功。迄今为止,最成功的是ONYX-015,这是一种基于腺病毒——它能导致最常见的感冒——的头颈癌治疗方法,这种疗法于2005年在中国被证明是有效的。美国宾夕法尼亚州匹兹堡大学的病毒学家Steve Thorne领导的一个研究小组于是便想搞清楚,牛痘病毒是否更适合于消灭癌症。

  研究人员首先剔除了牛痘病毒的两个基因,后者是病毒在正常细胞中生长所必需的。这样一来,病毒便只能在癌细胞内部生长。研究人员同时还在这种病毒中植入了1种基因,从而使其能够产生粒细胞—巨噬细胞集落刺激因子,它能够诱发机体免疫系统识别并攻击被病毒传染的肿瘤。

  当这种经过遗传改良的病毒被注射入患有肝癌并已向肺脏扩散的兔子中后,动物的肝脏肿瘤并没有扩大,而肺脏肿瘤则开始缩小。研究人员在10月25日的《临床研究》网络版上报告了这一研究成果。在那些没有接种病毒的试验动物体内,肝脏肿瘤增长了4倍,且新的肺脏肿瘤也向周围扩散。Thorne表示,通过更高剂量的病毒或与其他药物联合治疗,将有望全部去除癌细胞。Thorne已经同美国食品与药物管理局商讨,在癌症患者中进行这种病毒临床试验的可能性。他希望相关试验能够在明年早些时候开始。

  证明这种病毒的安全性将是研究人员需要完成的第一步。Thorne说,对人体组织进行的试验显示,该病毒并不会传染正常细胞,而其他安全措施——例如牛痘免疫球蛋白——将能够抵消由此产生的少量不良反应。

  宾夕法尼亚州费城福克斯·蔡斯癌症研究中心的医学肿瘤专家Louis  Weiner表示:“这是一个引人注目的方法,应该进行临床测试。”Weiner指出,与ONYX-015相比,牛痘病毒可能更有优势,包括更高的消灭肿瘤的功效等,但他强调,动物试验的结果往往很难在人体中推广,所以他对此表示审慎的乐观。(科学时报)

原始出处:

J. Clin. Invest. 117:3350-3358 (2007). doi:10.1172/JCI32727.
Copyright ©2007 by the American Society for Clinical Investigation

Rational strain selection and engineering creates a broad-spectrum, systemically effective oncolytic poxvirus, JX-963

Steve H. Thorne1,2, Tae-Ho H. Hwang3, William E. O’Gorman4, David L. Bartlett5, Shizuko Sei6, Femina Kanji7, Christopher Brown8, Joel Werier9, Jin-Han Cho10, Dong-Ewon Lee11, Yaohe Wang12, John Bell2,7 and David H. Kirn2

1Department of Pediatrics and Bio-X Program, James H. Clark Center, Stanford University School of Medicine, Stanford, California, USA. 2Jennerex Biotherapeutics, San Francisco, California, USA. 3Department of Pharmacology, Medical College of Dong-A University, Busan, Republic of Korea. 4Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California, USA. 5Division of Surgical Oncology, Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. 6Viral Vector Toxicology Section, LHTP, SAIC-Frederick Inc., National Cancer Institute–Frederick, Frederick, Maryland, USA. 7Ottawa Health Research Institute, Ottawa, Ontario, Canada. 8Biochemistry, Microbiology and Immunology Department, University of Ottawa, Ottawa, Ontario, Canada. 9Ottawa General Hospital, Ottawa, Ontario, Canada. 10Department of Radiology and 11Department of Pharmacology, Medical College of Dong-A University, Busan, Republic of Korea. 12Barts and the London School of Medicine and Dentistry, Queen Mary’s University of London, London, United Kingdom.

Address correspondence to: David H. Kirn, Jennerex Biotherapeutics, One Market Street, San Francisco, California 94105, USA. Phone: (415) 281-8886; Fax: (415) 598-2600; E-mail: dkirn@jennerex.com .

Received for publication May 18, 2007, and accepted in revised form August 15, 2007.

Replication-selective oncolytic viruses (virotherapeutics) are being developed as novel cancer therapies with unique mechanisms of action, but limitations in i.v. delivery to tumors and systemic efficacy have highlighted the need for improved agents for this therapeutic class to realize its potential. Here we describe the rational, stepwise design and evaluation of a systemically effective virotherapeutic (JX-963). We first identified a highly potent poxvirus strain that also trafficked efficiently to human tumors after i.v. administration. This strain was then engineered to target cancer cells with activation of the transcription factor E2F and the EGFR pathway by deletion of the thymidine kinase and vaccinia growth factor genes. For induction of tumor-specific cytotoxic T lymphocytes, we further engineered the virus to express human GM-CSF. JX-963 was more potent than the previously used virotherapeutic Onyx-015 adenovirus and as potent as wild-type vaccinia in all cancer cell lines tested. Significant cancer selectivity of JX-963 was demonstrated in vitro in human tumor cell lines, in vivo in tumor-bearing rabbits, and in primary human surgical samples ex vivo. Intravenous administration led to systemic efficacy against both primary carcinomas and widespread organ-based metastases in immunocompetent mice and rabbits. JX-963 therefore holds promise as a rationally designed, targeted virotherapeutic for the systemic treatment of cancer in humans and warrants clinical testing.

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