Abstract
Oncolytic adenoviruses (Ad) have shown promising results in the therapeutic treatment of cancer. Ad type 5 (Ad5) is the most extensively utilized Ad type. However, several limitations exist to using Ad5 as an oncolytic virus, including high levels of anti-Ad5 neutralizing antibodies in the population, binding of the Ad5 hexon to blood coagulation factor X leading to liver sequestration and toxicity, and reduced expression of the primary receptor CAR on many tumors. Here, we use in vitro methods to explore the oncolytic potential of four alternative Ad types (Ad26, 28, 45, and 48) belonging to the species D Ad subgroup and developed replication-competent species D Ads expressing the human sodium iodide symporter protein (hNIS) for combination radiovirotherapy. We evaluated the species D Ad vectors transduction, replication, cytotoxicity, and gene expression in six different cancer cell lines. Species D Ads showed the greatest transduction and cytotoxic killing in the SKBR3 breast cancer cells, followed by 293, A549, and HepG2 cells, however the cytotoxicity was less than the wild type Ad5 virus. In contrast, species D Ads showed limited transduction and cytotoxicity in the Hela and SKOV3 cancer cell lines. These species D Ad vectors also successfully expressed the hNIS gene during infection leading to increased iodide uptake in multiple cancer cell lines. These results, the low seroprevalence of anti-species D antibodies, and the lack of binding to blood coagulation FX, support further exploration of species D Ads as alternative oncolytic adenoviruses against multiple types of cancer.
Highlights
Oncolytic virotherapy, or the use of replication-competent viruses with a lytic life cycle to kill cancer cells, has promising therapeutic anticancer potential [1]
We developed four replication competent species D adenovirus (Ad) vectors to evaluate their oncolytic potential in the treatment of cancer
The E3 gene was replaced by the human iodide symporter gene to create a recombinant oncolytic virus as a candidate for radiovirotherapy (Figure 1)
Summary
The use of replication-competent viruses with a lytic life cycle to kill cancer cells, has promising therapeutic anticancer potential [1]. An estimated 50–90% of the adult population is seropositive for pre-existing anti-Ad5 neutralizing antibodies (NAbs) [4,5,6] These anti-Ad5 NAbs have previously been shown to limit the antitumor activity of the Ad5 type, especially during intravenous systemic delivery to treat metastatic lesions [7,8,9]. Ad5 uses the coxsackie-adenovirus receptor (CAR) which is often absent or downregulated in cancer cells [2,12,13,14,15]. Due to these limitations, researchers have begun exploring alternative Ad types for use as oncolytic viruses
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