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Utilizing the Antigen Capsid-Incorporation Strategy for the Development of Adenovirus Serotype 5-Vectored Vaccine Approaches
Published on: May 6, 2015
A novel oncolytic adenovirus based on simian adenovirus serotype 24
Tao Cheng1, Yufeng Song1, Yan Zhang1
1Vaccine Research Center, Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Science, Shanghai 200031, China.
Abstract:
Among the oncolytic virotherapy, an emerging treatment for tumor, adenoviruses are widely used at present in preclinical and clinical trials. Traditionally, oncolytic adenoviruses were developed based on the human adenovirus serotype 5 (AdHu5). However, AdHu5 has the drawbacks of preexisting anti-AdHu5 immunity in most populations, and extensive sequestration of Adhu5 by the liver through hexon, blood coagulation factor X (FX), and FX receptor interactions. To tackle these problems, we explored a novel oncolytic adenovirus AdC7-SP/E1A-ΔE3 for cancer treatment. AdC7-SP/E1A-ΔE3 was constructed by replacing the E1A promoter with tumor specific promoter survivin promoter and deleting E3 region using direct cloning methods based on simian adenovirus serotype 24 (namely AdC7). We showed that AdC7-SP/E1A-ΔE3 significantly killed tumor cell lines NCI-H508 and Huh7, and inhibited tumor growth in both NCI-H508 and Huh7 xenograft tumor models. Importantly, AdC7-SP/E1A-ΔE3 exhibited the antitumor efficacy via systemic administration. Mechanistically, infected cells were killed by AdC7-SP/E1A-ΔE3 via the p53-independent mitochondrial apoptosis pathway in which phosphorylation of BAD markedly declined and the expresses of Bik significantly went up. Therefore, AdC7-SP/E1A-ΔE3 is a promising candidate for liver and colon tumor treatment.
Insights
A novel oncolytic adenovirus, AdC7-SP/E1A-ΔE3, effectively treats liver and colon tumors. This engineered simian adenovirus overcomes limitations of human adenovirus serotype 5, showing significant antitumor efficacy in preclinical models.
Area of Science:
- Oncolytic Virotherapy
- Cancer Treatment
- Adenovirus Research
Background:
- Human adenovirus serotype 5 (AdHu5) is widely used in oncolytic virotherapy but faces challenges like pre-existing immunity and liver sequestration.
- Limitations of AdHu5 hinder its efficacy in cancer treatment, necessitating the development of alternative oncolytic adenoviruses.
Purpose of the Study:
- To develop and evaluate a novel oncolytic adenovirus, AdC7-SP/E1A-ΔE3, for enhanced cancer treatment.
- To overcome the limitations associated with traditional AdHu5-based oncolytic adenoviruses.
Main Methods:
- Engineered a novel oncolytic adenovirus, AdC7-SP/E1A-ΔE3, based on simian adenovirus serotype 24 (AdC7).
- Replaced the E1A promoter with the survivin promoter and deleted the E3 region using direct cloning.
- Evaluated the efficacy of AdC7-SP/E1A-ΔE3 in killing tumor cell lines (NCI-H508, Huh7) and inhibiting tumor growth in xenograft models.
Main Results:
- AdC7-SP/E1A-ΔE3 demonstrated significant tumor cell killing in vitro.
- In vivo studies showed inhibited tumor growth in NCI-H508 and Huh7 xenograft models.
- The adenovirus exhibited antitumor efficacy following systemic administration.
- Mechanism of action involves p53-independent mitochondrial apoptosis via BAD dephosphorylation and Bik upregulation.
Conclusions:
- AdC7-SP/E1A-ΔE3 is a promising oncolytic adenovirus for liver and colon tumor treatment.
- The engineered adenovirus overcomes AdHu5 limitations, offering improved therapeutic potential.
- The p53-independent apoptotic pathway highlights a novel mechanism for virotherapy.
