科學(xué)家發(fā)現(xiàn)，在天花的根除中起到重要作用的一種病毒在癌癥治療中也能夠大顯身手,。在一項(xiàng)新研究中,，一個(gè)轉(zhuǎn)基因牛痘株，即人們所說(shuō)的天花疫苗,，能夠抑制兔子肝臟腫瘤的生長(zhǎng),。如今，這種病毒正在向著進(jìn)行人體臨床試驗(yàn)的目標(biāo)邁進(jìn),。
10多年來(lái)，科學(xué)家一直試圖用經(jīng)過(guò)遺傳手段改良的病毒傳染并破壞癌細(xì)胞,，但只獲得了有限的成功,。迄今為止，最成功的是ONYX-015,，這是一種基于腺病毒——它能導(dǎo)致最常見(jiàn)的感冒——的頭頸癌治療方法,，這種療法于2005年在中國(guó)被證明是有效的。美國(guó)賓夕法尼亞州匹茲堡大學(xué)的病毒學(xué)家Steve Thorne領(lǐng)導(dǎo)的一個(gè)研究小組于是便想搞清楚,，牛痘病毒是否更適合于消滅癌癥,。
研究人員首先剔除了牛痘病毒的兩個(gè)基因，后者是病毒在正常細(xì)胞中生長(zhǎng)所必需的,。這樣一來(lái)，病毒便只能在癌細(xì)胞內(nèi)部生長(zhǎng),。研究人員同時(shí)還在這種病毒中植入了1種基因,，從而使其能夠產(chǎn)生粒細(xì)胞—巨噬細(xì)胞集落刺激因子,，它能夠誘發(fā)機(jī)體免疫系統(tǒng)識(shí)別并攻擊被病毒傳染的腫瘤。
當(dāng)這種經(jīng)過(guò)遺傳改良的病毒被注射入患有肝癌并已向肺臟擴(kuò)散的兔子中后,，動(dòng)物的肝臟腫瘤并沒(méi)有擴(kuò)大,，而肺臟腫瘤則開(kāi)始縮小。研究人員在10月25日的《臨床研究》網(wǎng)絡(luò)版上報(bào)告了這一研究成果,。在那些沒(méi)有接種病毒的試驗(yàn)動(dòng)物體內(nèi),，肝臟腫瘤增長(zhǎng)了4倍，且新的肺臟腫瘤也向周?chē)鷶U(kuò)散,。Thorne表示,，通過(guò)更高劑量的病毒或與其他藥物聯(lián)合治療，將有望全部去除癌細(xì)胞,。Thorne已經(jīng)同美國(guó)食品與藥物管理局商討,，在癌癥患者中進(jìn)行這種病毒臨床試驗(yàn)的可能性。他希望相關(guān)試驗(yàn)?zāi)軌蛟诿髂暝缧r(shí)候開(kāi)始,。
證明這種病毒的安全性將是研究人員需要完成的第一步,。Thorne說(shuō)，對(duì)人體組織進(jìn)行的試驗(yàn)顯示,，該病毒并不會(huì)傳染正常細(xì)胞,，而其他安全措施——例如牛痘免疫球蛋白——將能夠抵消由此產(chǎn)生的少量不良反應(yīng)。
賓夕法尼亞州費(fèi)城?？怂?middot;蔡斯癌癥研究中心的醫(yī)學(xué)腫瘤專(zhuān)家Louis Weiner表示：“這是一個(gè)引人注目的方法,，應(yīng)該進(jìn)行臨床測(cè)試。”Weiner指出,，與ONYX-015相比,，牛痘病毒可能更有優(yōu)勢(shì)，包括更高的消滅腫瘤的功效等,，但他強(qiáng)調(diào),，動(dòng)物試驗(yàn)的結(jié)果往往很難在人體中推廣，所以他對(duì)此表示審慎的樂(lè)觀,。（科學(xué)時(shí)報(bào)）
原始出處:
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: [email protected] .
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.
