Recent advances in genetic modification of adenovirus vectors for cancer treatment.
Recent advances in genetic modification of adenovirus vectors for cancer treatment.
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DOI：
10.1111/cas.13228
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发表时间：
2017-05
期刊：
影响因子：
5.7
通讯作者：
Aoki K
中科院分区：
文献类型：
--
作者：
Yamamoto Y;Nagasato M;Yoshida T;Aoki K
腺病毒被广泛用于将基因输送到各种类型的细胞中，并已被用于基因治疗和溶瘤病毒治疗的一些临床试验。然而，对于腺病毒载体的临床应用，必须解决几个问题。由于主要细胞受体的广泛分布，腺病毒载体选择性地将治疗性基因输送到靶肿瘤是不可能的。腺病毒的全身性给药导致肝脏趋向性不依赖于主要受体。腺病毒在体内可诱导强大的先天免疫和获得性免疫。此外，有必要对这些载体进行几次修饰，以增强其溶瘤活性并确保患者安全。因此，腺病毒基因组的设计就是为了克服这些问题。本综述的第一部分概述了用于癌症治疗的腺病毒载体的基因修饰的最新进展。此外，几个小组最近开发了癌症靶向腺病毒载体，方法是使用在纤维旋钮上显示随机多肽的文库。胰腺癌靶向序列已经被分离出来，我们的团队已经证明这些溶瘤载体在胰腺癌的细胞系、小鼠模型和外科标本中具有更高的基因转导效率和更强的溶瘤活性。在这篇综述的第二部分，我们解释了联合肿瘤靶向策略可能是一种有前景的方法来增加溶瘤腺病毒载体的临床实用性。
Adenoviruses are widely used to deliver genes to a variety of cell types and have been used in a number of clinical trials for gene therapy and oncolytic virotherapy. However, several concerns must be addressed for the clinical use of adenovirus vectors. Selective delivery of a therapeutic gene by adenovirus vectors to target cancer is precluded by the widespread distribution of the primary cellular receptors. The systemic administration of adenoviruses results in hepatic tropism independent of the primary receptors. Adenoviruses induce strong innate and acquired immunity in vivo. Furthermore, several modifications to these vectors are necessary to enhance their oncolytic activity and ensure patient safety. As such, the adenovirus genome has been engineered to overcome these problems. The first part of the present review outlines recent progress in the genetic modification of adenovirus vectors for cancer treatment. In addition, several groups have recently developed cancer‐targeting adenovirus vectors by using libraries that display random peptides on a fiber knob. Pancreatic cancer‐targeting sequences have been isolated, and these oncolytic vectors have been shown by our group to be associated with a higher gene transduction efficiency and more potent oncolytic activity in cell lines, murine models, and surgical specimens of pancreatic cancer. In the second part of this review, we explain that combining cancer‐targeting strategies can be a promising approach to increase the clinical usefulness of oncolytic adenovirus vectors.