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Published on: November 24, 2014
An acute toxicology study with INGN 007, an oncolytic adenovirus vector, in mice and permissive Syrian hamsters;
D L Lichtenstein1, J F Spencer, K Doronin
1VirRx, Inc., St Louis, MO 63104, USA.
Abstract:
Oncolytic (replication-competent) adenoviruses as anticancer agents provide new, promising tools to fight cancer. In support of a Phase I clinical trial, here we report safety data with INGN 007 (VRX-007), an oncolytic adenovirus with increased anti-tumor efficacy due to overexpression of the adenovirus-encoded ADP protein. Wild-type adenovirus type 5 (Ad5) and a replication-defective version of Ad5 were also studied as controls. A parallel study investigating the biodistribution of these viruses is described elsewhere in this issue. The toxicology experiments were conducted in two species, the Syrian hamster, which is permissive for INGN 007 and Ad5 replication and the poorly permissive mouse. The studies demonstrated that the safety profile of INGN 007 is similar to Ad5. Both viruses caused transient liver damage upon intravenous injection that resolved by 28 days post-infection. The No-Observable-Adverse-Effect-Level (NOAEL) for INGN 007 in hamsters was 3 x 10(10) viral particles per kg. In hamsters, the replication-defective vector caused less toxicity, indicating that replication of Ad vectors in the host is an important factor in pathogenesis. With mice, INGN 007 and Ad5 caused toxicity comparable to the replication-defective adenovirus vector. Partially based on these results, the FDA granted permission to enter into a Phase I clinical trial with INGN 007.
Insights
INGN 007, an oncolytic adenovirus, shows a safety profile similar to wild-type adenovirus type 5 in preclinical toxicology studies. These findings support the initiation of a Phase I clinical trial for this promising cancer therapy.
Area of Science:
- Oncolytic virotherapy
- Adenovirus vectors
- Cancer treatment
Background:
- Oncolytic adenoviruses are promising cancer agents.
- INGN 007 is an oncolytic adenovirus engineered for enhanced anti-tumor efficacy.
- Preclinical safety data is crucial for clinical trial progression.
Purpose of the Study:
- To evaluate the safety profile of INGN 007.
- To compare the toxicity of INGN 007 with wild-type adenovirus type 5 (Ad5) and a replication-defective Ad5 vector.
- To determine the No-Observable-Adverse-Effect-Level (NOAEL) for INGN 007.
Main Methods:
- Toxicology studies were conducted in Syrian hamsters and mice.
- Intravenous administration of viruses was used.
- Assessment of liver damage and overall toxicity was performed.
Main Results:
- INGN 007 demonstrated a safety profile comparable to Ad5 in both species.
- Transient liver toxicity was observed for both INGN 007 and Ad5, resolving within 28 days.
- Replication-defective vectors showed reduced toxicity in hamsters, highlighting the role of viral replication in pathogenesis.
Conclusions:
- INGN 007 exhibits an acceptable safety profile for clinical investigation.
- Viral replication is a key factor in adenovirus-mediated pathogenesis.
- These safety findings supported FDA approval for a Phase I clinical trial of INGN 007.
