Pre-clinical Assessment of C134, a Chimeric Oncolytic Herpes Simplex Virus, in Mice and Non-human Primates
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Published on: November 24, 2014
Kevin A Cassady1, David F Bauer2, Justin Roth3
1Department of Pediatrics, Research Institute Center for Childhood Cancer and Blood Disorders, Nationwide Children's Hospital, Columbus, OH 43212, USA; Ohio State University College of Medicine, Columbus, OH 43210, USA.
Abstract:
Oncolytic herpes simplex virus (oHSV) type I constructs are investigational anti-neoplastic agents for a variety of malignancies, including malignant glioma. Clinical trials to date have supported the safety of these agents even when directly administered in the CNS. Traditional pre-clinical US Food and Drug Administration (FDA) toxicity studies for these agents have included the use of two species, generally including murine and primate studies. Recently, the FDA has decreased its requirement of non-human primates as an animal model for ethical reasons, especially for established viral systems where there are good alternative model systems. Here we present data demonstrating the safety of C134, a chimeric oHSV construct, in CBA mice as well as in a limited number of the HSV-sensitive non-human primate Aotus nancymaae as a proposed agent for clinical trials. These data, along with the previously conducted clinical trials of oHSV constructs, support the use of the CBA mouse model as sufficient for the pre-clinical toxicity studies of this agent. We summarize our experience with different HSV recombinants and differences between them using multiple assays to assess neurovirulence, as well as our experience with C134 in a limited number of A. nancymaae.
Insights
Oncolytic herpes simplex virus (oHSV) constructs show promise for treating brain tumors. New data suggest CBA mice are a sufficient model for pre-clinical safety testing, reducing the need for non-human primates in oHSV toxicity studies.
Area of Science:
- Oncolytic virotherapy
- Neuro-oncology
- Pre-clinical toxicology
Background:
- Oncolytic herpes simplex virus (oHSV) type I constructs are under investigation as anti-cancer agents for brain malignancies.
- Clinical trials indicate oHSV agents are safe when administered directly into the central nervous system (CNS).
- Traditional pre-clinical toxicity studies require two animal species, often including non-human primates, but regulatory agencies are reducing this requirement for ethical reasons and when alternative models exist.
Purpose of the Study:
- To evaluate the safety of C134, a chimeric oHSV construct, in CBA mice and a limited number of non-human primates (Aotus nancymaae).
- To support the use of the CBA mouse model as adequate for pre-clinical toxicity studies of oHSV agents.
- To summarize experience with different HSV recombinants and assess the neurovirulence of C134.
Main Methods:
- Safety assessment of C134 in CBA mice.
- Safety assessment of C134 in a limited cohort of HSV-sensitive non-human primates (Aotus nancymaae).
- Neurovirulence assays for various HSV recombinants and C134.
Main Results:
- Data demonstrate the safety of the C134 oHSV construct in CBA mice.
- Limited data indicate safety of C134 in Aotus nancymaae.
- Previous clinical trials and current pre-clinical data support the sufficiency of the CBA mouse model for oHSV toxicity studies.
Conclusions:
- The CBA mouse model is sufficient for pre-clinical toxicity studies of oHSV agents like C134.
- Reduced reliance on non-human primates for oHSV toxicity testing is feasible.
- Further clinical trials of C134 are supported by these safety findings.
