Directed evolution generates a novel oncolytic virus for the treatment of colon cancer.
Directed evolution generates a novel oncolytic virus for the treatment of colon cancer.
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定向进化产生了一种新型的溶瘤病毒，用于治疗结肠癌。
DOI：
10.1371/journal.pone.0002409
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发表时间：
2008-06-18
期刊：
影响因子：
3.7
通讯作者：
Hermiston, Terry W.
中科院分区：
文献类型：
--
作者：
Kuhn, Irene;Harden, Paul;Bauzon, Maxine;Chartier, Cecile;Nye, Julie;Thorne, Steve;Reid, Tony;Ni, Shaoheng;Lieber, Andre;Fisher, Kerry;Seymour, Len;Rubanyi, Gabor M.;Harkins, Richard N.;Hermiston, Terry W.
病毒介导的溶瘤是一种新型的癌症治疗方法，由于药物在肿瘤细胞中的选择性生长和扩增，其具有比现有疗法更有效且毒性更低的潜力。迄今为止，这些药物在患者中高度安全，但通常达不到其作为单一疗法的预期治疗价值。因此，需要产生高效溶瘤病毒的新方法。为了满足这一需求，我们开发了一种新的方法，我们称之为“定向进化”，用于创建高效的溶瘤病毒。采用“定向进化”方法，通过汇集一系列血清型，然后在引起血清型之间重组的条件下传代汇集物来增加病毒多样性。然后将这些高度多样化的病毒库置于严格的定向选择下，以产生和鉴定高度有效的药剂。ColoAd 1是一种复杂的Ad 3/Ad 11 p嵌合病毒，是通过这种新方法获得的最初的溶瘤病毒。ColoAd 1是第一个描述的基于非Ad 5的溶瘤Ad，在体外比亲本血清型或临床上最先进的溶瘤Ad ONYX-015的效力和选择性高2-3个对数。在静脉内注射后，在结肠癌肝转移异种移植模型中进一步体内测试ColoAd 1的功效，并且在来源于人结肠直肠肿瘤组织上证明其离体选择性。最后，我们证明了用外源基因武装ColoAd 1的能力，建立了从单一药物在多个水平上影响癌症治疗的潜力。使用“定向进化”方法，我们已经产生了ColoAd 1，一种新型的嵌合溶瘤病毒。在体外，当与ONYX-015相比时，该病毒在结肠癌细胞上表现出>2 log的效力和选择性增加。这些结果得到了体内和离体研究的进一步支持。此外，这些结果已经验证了这种方法作为一种新的通用方法，用于获得临床相关的，高效的抗癌病毒疗法。
Viral-mediated oncolysis is a novel cancer therapeutic approach with the potential to be more effective and less toxic than current therapies due to the agents selective growth and amplification in tumor cells. To date, these agents have been highly safe in patients but have generally fallen short of their expected therapeutic value as monotherapies. Consequently, new approaches to generating highly potent oncolytic viruses are needed. To address this need, we developed a new method that we term “Directed Evolution” for creating highly potent oncolytic viruses. Taking the “Directed Evolution” approach, viral diversity was increased by pooling an array of serotypes, then passaging the pools under conditions that invite recombination between serotypes. These highly diverse viral pools were then placed under stringent directed selection to generate and identify highly potent agents. ColoAd1, a complex Ad3/Ad11p chimeric virus, was the initial oncolytic virus derived by this novel methodology. ColoAd1, the first described non-Ad5-based oncolytic Ad, is 2–3 logs more potent and selective than the parent serotypes or the most clinically advanced oncolytic Ad, ONYX-015, in vitro. ColoAd1's efficacy was further tested in vivo in a colon cancer liver metastasis xenograft model following intravenous injection and its ex vivo selectivity was demonstrated on surgically-derived human colorectal tumor tissues. Lastly, we demonstrated the ability to arm ColoAd1 with an exogenous gene establishing the potential to impact the treatment of cancer on multiple levels from a single agent. Using the “Directed Evolution” methodology, we have generated ColoAd1, a novel chimeric oncolytic virus. In vitro, this virus demonstrated a >2 log increase in both potency and selectivity when compared to ONYX-015 on colon cancer cells. These results were further supported by in vivo and ex vivo studies. Furthermore, these results have validated this methodology as a new general approach for deriving clinically-relevant, highly potent anti-cancer virotherapies.
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