Cancer Scene Investigation: How a Cold Virus Became a Tumor Killer

Abstract

Oncolytic therapy is a novel anticancer treatment with attenuated lytic viruses such as adenovirus (Ad). These viruses kill the host cells through their lytic replication cycle and are thus distinct from classical gene therapy viruses, which serve as gene delivery agents and do not replicate. Oncolytic Ads are genetically engineered so as to replicate only in cancer cells. Their replication cycle leads to viral multiplication, the killing of the host cells and spreading of the infection throughout the tumor. Following success in preclinical studies, their anti-tumor potential is now being evaluated in the clinic. Three oncolytic Ads (dl1520, Ad5-CD/TKrep, and CV706) have completed Phase I and II clinical trials in cancer patients where their administration via multiple routes and in combination with chemo- or radiotherapies, has demonstrated overall safety. These viruses are being re-engineered to arm them with additional therapeutic genes, bolstering their oncolytic activity with a bystander effect. For example, Ad5-CD/TKrep delivers a therapeutic prodrug-activating (suicide) gene. These data indicate that oncolytic Ads are a promising novel cancer treatment approach that can be combined with other modalities, such as gene therapy and classical chemo- and radiotherapies. Further improvements to enhance their specificity, targeting and oncolytic activity are needed however, as these first-generation viruses showed modest anti-tumor activity. To improve their efficacy in the clinic, it will be important to devise and incorporate novel monitoring techniques in the clinical trials, such as analysis of viral replication in biopsies and through the use of creative noninvasive imaging technologies.

Targeted Cancer Gene Therapy Using a Hypoxia Inducible Factor–Dependent Oncolytic Adenovirus Armed with Interleukin-4

“…The replicative capacity of HYPR-Ad-IL4 in vitro was attenuated 10-to 100-fold compared with dl309-Ad depending on the cell line tested ( Table 1). The reasons for this are currently unknown but may in part relate to differences in the E3 gene region between the two viruses (11). Despite this, HYPR-Ad-IL4 was able to effectively induce cytolysis in vitro, and most importantly, its in vivo antitumor activity was equivalent to dl309-Ad.…”

“…The underlying principle for this developing cancer therapy is that the virus will selectively replicate in tumor cells, resulting in an exponential increase of the virus inoculum and the establishment of repeating cycles of cell infection, virus replication, and tumor cell death. Treatment of cancer patients with oncolytic Ads in clinical trials has shown the overall safety of this therapy and modest antitumor activity (11). The differential activation of HIF/HRE-dependent gene expression in tumors compared with normal tissue provides an opportunity for the design of a targeted oncolytic Ad that would depend on HIF expression for its replication.…”

ODE models for oncolytic virus dynamics

“…Cancer therapy by means of oncolytic viruses has attracted attention of clinicians, wet lab oncologists and mathematical modelers (Bell, 2007; Bell et al, 2003; Crompton and Kirn, 2007; Davis and Fang, 2005; Kaplan, 2005; Kelly and Russell, 2007; Kirn and McCormick, 1996; McCormick, 2003; McCormick, 2005; Novozhilov et al, 2006; O'Shea, 2005; Parato et al, 2005; Post et al, 2005; Roberts et al, 2006; Vaha-Koskela et al, 2007; Wodarz, 2001; Wodarz, 2003). The idea behind this treatment is to infect a tumor with engineered viruses which specifically infect and kill tumor cells, and have the potential to spread throughout the tumor.…”

Yeast Cytosine Deaminase Mutants with Increased Thermostability Impart Sensitivity to 5-Fluorocytosine

“…Inhibition of TS blocks dTTP production and prevents DNA synthesis 5-7 . The CD/5FC system has been used in numerous animal models 8-10 and is currently being evaluated in clinical trials for solid tumors [11][12][13][14][15] . One limitation to this approach is the poor transfection efficiency of current vector delivery systems.…”