Recent advances in genetic modification of adenovirus vectors for cancer treatment

Abstract

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.

Keywords: Adenovirus; fiber knob; library; pancreatic cancer; targeting.

Figure 1

Genetic modification of recombinant adenovirus vectors. Mutations in the E1 region are introduced or the E1 gene is transcribed by a tumor‐ or tissue‐specific promoter to restrict viral replication to targeted cancer cells, without affecting normal cells. The arginine‐glycine‐aspartic acid (RGD) sequence in the penton base is depleted and mutation in the AB‐loop of the fiber knob is induced to suppress naïve tropism. Ligands are inserted into the HI‐loop and AB‐loop of the fiber to target cancer cells. The hypervariable region of the hexon is replaced to inhibit interaction with coagulation factor. Organ‐specific microRNA (miRNA) targeting sequences are inserted into the E4 region to suppress tissue damage that results from immune reactions. Marker genes such as enhanced green fluorescent protein are inserted in the deleted E3 region for visualization.

Figure 2

Development of pancreatic cancer‐targeting oncolytic virus by a library approach. The pancreatic cancer‐targeting sequence is combined with a survivin promoter‐driven oncolytic adenovirus (AdSur‐SYE). Locally advanced pancreatic cancer is surgically unresectable but can be accessed by ultrasound‐ or computed tomography‐guided percutaneous injection or endoscopic ultrasound‐guided injection of viruses.

Figure 3

Future directions for oncolytic virus research. In future, the five characteristics would be required for progress in the development of oncolytic viruses.