Oncolytic viruses: adenoviruses

Abstract

Tumor-selectively replicating (oncolytic) viruses are promising tools for therapy of solid cancers and have been initially developed to achieve potent tumor lysis with acceptable side effects on healthy tissue. However, in recent years, oncolytic viruses have been recognized as therapeutic vehicles exhibiting multipronged anti-tumoral activity. Apart from direct cytolysis, stimulation of both innate and adaptive tumor-directed immune responses have been recognized as important mechanisms of oncolytic virotherapy, which were probably decisive in achieving the long-term tumor remissions that oncolytic viruses have shown in clinical trials in advanced melanoma. In this short review, we will introduce basic mechanisms of viral oncolysis and the current state of clinical development. With a focus on oncolytic adenoviruses, we will describe the efforts to restrict oncolytic virus infection to tumor tissue using conditional replication and targeted delivery. Furthermore, we will discuss ways to optimize virus-mediated immunostimulation and the potential of virotherapy as an integrative part of systemic tumor immunotherapies.

Development of oncolytic virotherapy: from genetic modification to combination therapy

“…Inserting targeting peptides can improve the entry efficiency of OVs [81]. For example, adenovirus type 5 (Ad5) is a widely used OV vector, but its receptor, coxsackie adenovirus receptor (CAR), is not highly expressed in many tumor cells [22]; this phenomenon leads to the low entry efficiency of OAd. Through genetic engineering, an arginine-glycine-aspartic acid (RGD) motif was inserted into the fiber knob domain of Ad5 to generate a newly modified virus, which no longer depends on CAR to enter tumor cells and instead relies on integrins that are highly expressed on tumor cells, to enter tumor cells [82].…”

Modeling the Efficacy of Oncolytic Adenoviruses In Vitro and In Vivo: Current and Future Perspectives

“…OAds selectively lyse tumor cells, disrupt the tumor microenvironment, and reactivate the immune system. Clinically, OAds have demonstrated a good safety profile and may address many of the most intractable obstacles to successful treatment of solid tumors [5].…”

Effect of Transgene Location, Transcriptional Control Elements and Transgene Features in Armed Oncolytic Adenoviruses

“…To increase the efficacy of oncolytic adenoviruses major research efforts have been directed to enhance tumor-targeting by capsid modifications, and tumor-selective replication using promoters and gene deletions. These aspects have been broadly reviewed in the literature [4][5][6]. Replication-selective oncolytic adenoviruses (OAds) with these modifications, such as CV706, CG7870, AdD24RGD, and ICOVIR5, entered clinical trials.…”