Going viral: a review of replication-selective oncolytic adenoviruses

Abstract

Oncolytic viruses have had a tumultuous course, from the initial anecdotal reports of patients having antineoplastic effects after natural viral infections a century ago to the development of current cutting-edge therapies in clinical trials. Adenoviruses have long been the workhorse of virotherapy, and we review both the scientific and the not-so-scientific forces that have shaped the development of these therapeutics from wild-type viral pathogens, turning an old foe into a new friend. After a brief review of the mechanics of viral replication and how it has been modified to engineer tumor selectivity, we give particular attention to ONYX-015, the forerunner of virotherapy with extensive clinical testing that pioneered the field. The findings from those as well as other oncolytic trials have shaped how we now view these viruses, which our immune system has evolved to vigorously attack, as promising immunotherapy agents.

Keywords: adenovirus; immunotherapy; oncology; oncolytic virus.

Figure 1. The major capsid proteins fiber, penton, and hexon are the principle mediators of binding to the host cell

Figure 2. The p53-MDM2-p14^ARF feedback loop

MDM2 negatively regulates p53 by promoting p53 degradation. p14^ARF (p19^ARF in the mouse) binds to and sequesters MDM2, thereby preventing MDM2 from targeting p53 for degradation while p53 negatively regulates p14^ARF expression. E1B-55kDa binds to and degrades p53. The removal of this gene in the ONYX-015 virus did not necessarily relieve p53 inhibition due to the presence of the other two components of the feedback loop in the tumor: MDM2 and p14^ARF.

Figure 3. CT scans of a patient receiving ONYX-015

This patient received treatment with ONYX-015 on days 1 and 8 and CT scans are shown from baseline, Day 21, 4 months and 13 months. The baseline CT scan of this patient demonstrates extensive disease in all lobes of the liver. The CT on day 21 demonstrates therapy-related enlargement of the tumor masses so-called pseudoprogression. The patient continued with monthly treatment with ONYX-015 in combination with 5-FU/leucovorin and improvement of the tumor masses (white arrows) was observed at 4 months. The masses (white arrows) have largely resolved by 13 months [88].

Figure 4. Times are trough all over

The expectation (hype)-disappointment cycle in virotherapy. Throughout its history, oncolytic virotherapy (OV) has been characterized by over-enthusiasm followed by pessimism and apathy when expectations were not met. With the immunotherapy revolution interest in OV has rebounded.