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Oncolytic adenovirus Ad657 for systemic virotherapy against prostate cancer
Tien V Nguyen1, Catherine M Crosby2, Gregory J Heller3
1Department of Internal Medicine, Division of Infectious Diseases.
Background:
Human species C adenovirus serotype 5 (Ad5) is the archetype oncolytic adenovirus and has been used in the vast majority of preclinical and clinical tests. While Ad5 can be robust, species C Ad6 has lower seroprevalence, side effects, and appears to be more potent as a systemic therapy against a number of tumors than Ad5. Historically, there have only been four species C human adenoviruses: serotypes 1, 2, 5, and 6. More recently a new species C adenovirus, Ad57, was identified. Ad57 is most similar to Ad6 with virtually all variation in their capsid proteins occurring in the hypervariable regions (HVRs) of their hexon proteins. Most adenovirus neutralizing antibodies target the HVRs on adenoviruses. This led us to replace the hexon HVRs in Ad6 with those from Ad57 to create a new virus called Ad657 and explore this novel species C platform's utility as an oncolytic virus.
Methods:
The HVR region from Ad57 was synthesized and used to replace the Ad6 HVR region by homologous recombination in bacteria generating a new viral platform that we call Ad657. Replication-competent Ad5, Ad6, and Ad657 were compared in vitro and in vivo for liver damage and oncolytic efficacy against prostate cancers after single intravenous treatment in mice.
Results:
Ad5, Ad6, and Ad657 had similar in vitro oncolytic activity against human prostate cancer cells. Ad5 provoked the highest level of liver toxicity after intravenous injection and Ad657 caused the least damage in mice. Previous data demonstrated that Ad6 was superior to Ad5 at killing distant subcutaneous prostate cancer tumors in mouse models after a intravenous injection. Given this, Ad657 was compared to the Ad6 benchmark virus by single intravenous injection into mice bearing subcutaneous human DU145 prostate cancers. Under these conditions, Ad657 first infected the liver and then reached distant tumors. Both Ad6 and Ad657 mediated significant delays in tumor growth and extension of survival with Ad6 mediating higher efficacy.
Conclusions:
These data suggest that Ad657 may have utility as a local or systemic oncolytic virotherapy for prostate cancers. These data also lay the foundation for serotype-switching with oncolytic species C Ads.
Insights
A new oncolytic virus, Ad657, engineered from species C adenoviruses, shows promise for prostate cancer treatment with reduced liver toxicity compared to Ad5. Further research is warranted for its therapeutic potential.
Area of Science:
- Oncolytic virotherapy
- Adenovirus research
- Cancer treatment
Background:
- Human species C adenovirus serotype 5 (Ad5) is a common oncolytic adenovirus.
- Species C Ad6 demonstrates greater potency and lower toxicity than Ad5 for systemic cancer therapy.
- Ad57, a newly identified species C adenovirus, shares similarities with Ad6, differing primarily in hexon hypervariable regions (HVRs).
Purpose of the Study:
- To engineer a novel oncolytic adenovirus, Ad657, by replacing Ad6 hexon HVRs with those from Ad57.
- To evaluate the utility of this new species C adenovirus platform for oncolytic virotherapy.
- To compare the efficacy and toxicity of Ad657 against Ad5 and Ad6 in preclinical models of prostate cancer.
Main Methods:
- Ad657 was generated by synthesizing Ad57 HVRs and replacing the Ad6 HVR region via homologous recombination in bacteria.
- Replication-competent Ad5, Ad6, and Ad657 were assessed in vitro for oncolytic activity against prostate cancer cells.
- In vivo studies in mice compared liver damage and oncolytic efficacy of Ad5, Ad6, and Ad657 following intravenous administration for prostate cancer treatment.
Main Results:
- Ad5, Ad6, and Ad657 exhibited similar in vitro oncolytic activity against human prostate cancer cells.
- Ad5 caused the highest liver toxicity, while Ad657 demonstrated the least liver damage in mice.
- Both Ad6 and Ad657 significantly delayed tumor growth and extended survival in mice with prostate cancer, with Ad6 showing higher efficacy.
Conclusions:
- Ad657 shows potential as a local or systemic oncolytic virotherapy for prostate cancers.
- The findings support the feasibility of serotype-switching for developing novel oncolytic species C adenoviruses.
- Ad657 represents a promising candidate for further investigation in oncolytic virotherapy strategies.
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