A novel oncolytic adenovirus based on simian adenovirus serotype 24.

Tao Cheng,Yufeng Song,Jieyun Yin,Dongming Zhou,Yan Zhang,Chao Zhang,Yudan Chi

doi:10.18632/oncotarget.15845

Abstract

Among the oncolytic virotherapy, an emerging treatment for tumor, adenoviruses are widely used at present in preclinical and clinical trials. Traditionally, oncolytic adenoviruses were developed based on the human adenovirus serotype 5 (AdHu5). However, AdHu5 has the drawbacks of preexisting anti-AdHu5 immunity in most populations, and extensive sequestration of Adhu5 by the liver through hexon, blood coagulation factor X (FX), and FX receptor interactions. To tackle these problems, we explored a novel oncolytic adenovirus AdC7-SP/E1A-ΔE3 for cancer treatment. AdC7-SP/E1A-ΔE3 was constructed by replacing the E1A promoter with tumor specific promoter survivin promoter and deleting E3 region using direct cloning methods based on simian adenovirus serotype 24 (namely AdC7). We showed that AdC7-SP/E1A-ΔE3 significantly killed tumor cell lines NCI-H508 and Huh7, and inhibited tumor growth in both NCI-H508 and Huh7 xenograft tumor models. Importantly, AdC7-SP/E1A-ΔE3 exhibited the antitumor efficacy via systemic administration. Mechanistically, infected cells were killed by AdC7-SP/E1A-ΔE3 via the p53-independent mitochondrial apoptosis pathway in which phosphorylation of BAD markedly declined and the expresses of Bik significantly went up. Therefore, AdC7-SP/E1A-ΔE3 is a promising candidate for liver and colon tumor treatment.

Highlights

Cancer remains a leading cause of death worldwide
AdC7-SP/E1A-ΔE3 is an oncolytic adenovirus in which E1A expression is driven by a survivin promoter and the E3 region is deleted; AdC7-ΔE3 is a modified adenovirus without the E3 region; and AdC7-ΔE1-ΔE3 is a non-replicating adenovirus lacking the E1 and E3 regions
To circumvent preexisting anti-human adenovirus serotype 5 (AdHu5) immunity in populations, chimpanzee adenoviruses have been engineered into replication-deficient vaccine vectors [25]

Summary

Introduction

Cancer remains a leading cause of death worldwide. The complexity of tumor and the acquired or inherent resistance to treatments [1] contribute to less efficiency of traditional treatment of cancer, including surgery, chemotherapy and radiotherapy, which are not feasible for patients with advanced stage [2]. Cancer virotherapy, which employs a conditionally replicative virus, has attracted considerable attention, because it can kill cancer cells, but not normal cells, by selectively replicating in and transmitting among cancer cells [3]. Among oncolytic viruses currently explored to treat cancer, adenoviruses are the most widely used. Oncolytic adenoviruses are engineered to selectively replicate in and kill tumor cells using different strategies. By virtue of its deleted E1B 55KDa gene, Onxy-015 was the first reported oncolytic adenovirus designed to replicate exclusively in p53-deleted or mutated cells [4]. The binding of EA1 to pRb protein through the CR2 region of E1A gene was required for adenovirus replication in normal cells rather than in tumor cells, and Ad5-Δ24 selectively replicate in tumor cells by deleting the CR2 region[5]. Oncolytic adenoviruses were constructed by replacing viral promoters with tumorspecific promoters such as survivin promoter [6], PSA promoter [7], or telomerase promoter [8]

Methods

Results

Conclusion