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Published on: November 24, 2014
Species D Adenoviruses as Oncolytic Viral Vectors
Brianna L Bullard1, Brigette N Corder1, Eric A Weaver1
1Nebraska Center for Virology, School of Biological Sciences, University of Nebraska, Lincoln, NE 68503, USA.
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.
Insights
Alternative adenoviruses (Ads) from species D show potential for cancer treatment. These viruses exhibit tumor cell targeting and gene expression, offering a promising alternative to Ad type 5 (Ad5) due to lower pre-existing immunity.
Area of Science:
- Oncolytic virotherapy
- Adenovirus research
- Cancer treatment modalities
Background:
- Oncolytic adenoviruses (Ads) show promise in cancer therapy, with Adenovirus type 5 (Ad5) being widely used.
- Limitations of Ad5 include pre-existing population immunity, liver toxicity due to Factor X binding, and low CAR receptor expression on tumors.
- Alternative Ad serotypes are needed to overcome Ad5 limitations for effective cancer treatment.
Purpose of the Study:
- To investigate the oncolytic potential of four species D Adenovirus types (Ad26, Ad28, Ad45, Ad48).
- To develop replication-competent species D Ads expressing the human sodium iodide symporter (hNIS) for radiovirotherapy.
- To evaluate species D Ad vectors' transduction, replication, cytotoxicity, and gene expression in various cancer cell lines.
Main Methods:
- In vitro evaluation of four species D Adenovirus types (Ad26, Ad28, Ad45, Ad48).
- Development of replication-competent species D Ads engineered to express the hNIS gene.
- Assessment of viral transduction, replication, cytotoxicity, and hNIS gene expression in six human cancer cell lines.
Main Results:
- Species D Ads demonstrated significant transduction and cytotoxic effects in SKBR3 breast cancer cells, followed by 293, A549, and HepG2 cells.
- Cytotoxicity of species D Ads was generally lower than wild-type Ad5, with limited efficacy in HeLa and SKOV3 cells.
- Species D Ad vectors successfully expressed the hNIS gene, enhancing iodide uptake in multiple cancer cell lines.
Conclusions:
- Species D Adenoviruses show potential as alternative oncolytic viruses, with notable efficacy in specific cancer cell lines.
- The developed species D Ads expressing hNIS enable combination radiovirotherapy, indicated by increased iodide uptake.
- Low seroprevalence of anti-species D antibodies and lack of Factor X binding suggest species D Ads are promising candidates for further cancer treatment research.
