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Published on: November 24, 2014
An E1B-19 kDa gene deletion mutant adenovirus demonstrates tumor necrosis factor-enhanced cancer selectivity and
Ta-Chiang Liu1, Gunnel Hallden, Yaohe Wang
1Viral and Genetic Therapy Program, Cancer Research UK, Imperial College Faculty of Medicine, London, UK.
Abstract:
Oncolytic adenoviruses hold promise as a new treatment platform for cancer, but limitations have been identified, including limited spread and potency. The adenoviral protein E1B-19 kDa is a Bcl-2 homologue that blocks apoptosis induction via the intrinsic and extrinsic pathways, specifically including tumor necrosis factor-mediated cell death. We demonstrate that an E1B-19 kDa gene deletion mutant had tumor necrosis factor-enhanced cancer selectivity, in vitro and in vivo, due to genetic blocks in apoptosis pathways in cancer cells. In addition, this mutant demonstrated significantly enhanced viral spread and antitumoral potency relative to dl1520 (aka Onyx-015) and wild-type adenovirus in vitro. Significant antitumoral efficacy was demonstrated in vivo by intratumoral and intravenous routes of administration. E1B-19 kDa deletion should be considered as a feature of oncolytic adenoviruses to enhance their safety, spread, and efficacy.
Insights
Deleting the E1B-19 kDa gene from oncolytic adenoviruses enhances tumor necrosis factor-mediated cancer selectivity, viral spread, and potency. This modification improves oncolytic adenovirus safety and efficacy for cancer treatment.
Area of Science:
- Oncolytic virotherapy
- Cancer biology
- Virology
Background:
- Oncolytic adenoviruses are a promising cancer treatment but face limitations in spread and potency.
- The adenoviral E1B-19 kDa protein, a Bcl-2 homologue, inhibits apoptosis, including tumor necrosis factor (TNF)-mediated cell death.
Purpose of the Study:
- To investigate the impact of E1B-19 kDa gene deletion on oncolytic adenovirus selectivity, spread, and antitumoral potency.
- To evaluate the potential of E1B-19 kDa deletion as a strategy to enhance oncolytic adenovirus efficacy.
Main Methods:
- Construction and characterization of an E1B-19 kDa gene deletion mutant adenovirus.
- In vitro and in vivo assessment of cancer cell selectivity, viral spread, and antitumoral efficacy.
- Comparison with wild-type adenovirus and dl1520 (Onyx-015).
Main Results:
- The E1B-19 kDa deletion mutant exhibited enhanced TNF-mediated cancer selectivity in vitro and in vivo.
- This mutant showed significantly improved viral spread and antitumoral potency compared to dl1520 and wild-type adenovirus.
- Significant in vivo antitumoral efficacy was observed via intratumoral and intravenous administration.
Conclusions:
- E1B-19 kDa deletion enhances oncolytic adenovirus selectivity by exploiting apoptosis pathway defects in cancer cells.
- This genetic modification improves viral spread and antitumoral potency, offering a potential strategy to boost oncolytic adenovirus efficacy and safety.
