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Published on: November 24, 2014
Preclinical Safety Studies of Enadenotucirev, a Chimeric Group B Human-Specific Oncolytic Adenovirus
Sam Illingworth1, Ying Di2, Maxine Bauzon3
1PsiOxus Therapeutics Ltd., Abingdon OX14 4SD, UK.
Abstract:
Enadenotucirev is an oncolytic group B adenovirus identified by a process of bio-selection for the ability to selectively propagate in and rapidly kill carcinoma cells. It is resistant to inactivation by human blood components, potentially enabling intravenous dosing in patients with metastatic cancer. However, there are no known permissive animal models described for group B adenoviruses that could facilitate a conventional approach to preclinical safety studies. In this manuscript, we describe our tailored preclinical strategy designed to evaluate the key biological properties of enadenotucirev. As enadenotucirev does not replicate in animal cells, a panel of primary human cells was used to evaluate enadenotucirev replication selectivity in vitro, demonstrating that virus genome levels were >100-fold lower in normal cells relative to tumor cells. Acute intravenous tolerability in mice was used to assess virus particle-mediated toxicology and effects on innate immunity. These studies showed that particle toxicity could be ameliorated by dose fractionation, using an initial dose of virus to condition the host such that cytokine responses to subsequent doses were significantly attenuated. This, in turn, supported the initiation of a phase I intravenous clinical trial with a starting dose of 1 × 1010 virus particles given on days 1, 3, and 5.
Insights
Enadenotucirev, an oncolytic adenovirus, selectively targets and kills carcinoma cells. Preclinical studies in human cells and mice demonstrated its safety and efficacy for intravenous administration in cancer patients.
Area of Science:
- Oncology
- Virology
- Gene Therapy
Background:
- Enadenotucirev is an oncolytic adenovirus engineered to target and destroy carcinoma cells.
- Its resistance to blood inactivation allows for potential intravenous delivery in metastatic cancer patients.
- Lack of permissive animal models for group B adenoviruses necessitates alternative preclinical evaluation strategies.
Purpose of the Study:
- To develop and implement a tailored preclinical strategy for evaluating the biological properties of enadenotucirev.
- To assess the selective replication of enadenotucirev in tumor cells versus normal cells.
- To determine the intravenous tolerability and immunomodulatory effects of enadenotucirev in a preclinical setting.
Main Methods:
- In vitro selectivity was assessed using a panel of primary human cells to evaluate enadenotucirev replication in normal versus tumor cells.
- Intravenous tolerability and innate immune responses were studied in mice.
- Dose fractionation was employed to mitigate particle toxicity and attenuate cytokine responses.
Main Results:
- Enadenotucirev demonstrated >100-fold lower virus genome levels in normal cells compared to tumor cells in vitro.
- Acute intravenous administration in mice revealed particle toxicity that could be managed through dose fractionation.
- Dose fractionation attenuated host cytokine responses, enabling subsequent virus administration.
Conclusions:
- The developed preclinical strategy effectively evaluated enadenotucirev's key biological properties.
- Findings supported the initiation of a Phase I clinical trial for intravenous administration of enadenotucirev.
- Enadenotucirev shows promise as an oncolytic virus for cancer therapy.
