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Published on: November 16, 2012
Molecular Pathology Methods to Characterize Biodistribution and Pharmacodynamics of the Oncolytic Virus VSV-GP in a
Andrea Matter1,2, Karol Budzik1, Saurin Mehta1
1Nonclinical Drug Safety, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut, USA.
Abstract:
Replication-competent oncolytic virus (OV) therapies are a promising new modality for cancer treatment. However, they pose unique challenges for preclinical assessment, due in part to their tumor specificity and ability to self-replicate in vivo. Understanding biodistribution, immune cell responses, and potential effects of intratumoral replication on these outcomes are important aspects of the nonclinical profile for OVs. Herein, a single intravenous dose of vesicular stomatitis virus pseudotyped with the glycoprotein of lymphocytic choriomeningitis virus (VSV-GP), or a cargo-expressing variant (VSV-GP-[cargo]), was examined in both tumor-free and CT26.CL25.IFNAR-/- syngeneic tumor-bearing mouse models. Biodistribution and immune cell responses were characterized using different molecular pathology methods, including a strand-specific in situ hybridization method to differentiate administered viral genomes from replicated or transcribed viral anti-genome RNA. We identified distinct patterns of viral biodistribution and replication across tumor and nontumor sites but no major differences in biodistribution, off-tumor cell tropism, or immune cell responses between tumor-free and tumor-bearing mouse models. Our findings characterize key cellular changes following systemic exposure to VSV-GP, provide a better understanding of a nonclinical permissive tumor model for OV assessment, and demonstrate how current molecular pathology methods can provide a bridge between traditional biodistribution and pathology readouts.
Insights
Replication-competent oncolytic viruses (OVs) show promise for cancer treatment. This study found similar biodistribution and immune responses in tumor-free and tumor-bearing mice, aiding preclinical OV assessment.
Area of Science:
- Oncology
- Virology
- Immunology
Background:
- Replication-competent oncolytic viruses (OVs) offer a novel cancer therapy approach.
- Assessing OV tumor specificity, replication, biodistribution, and immune responses is crucial for preclinical evaluation.
Purpose of the Study:
- To investigate the biodistribution and immune cell responses to systemically administered vesicular stomatitis virus pseudotyped with the glycoprotein of lymphocytic choriomeningitis virus (VSV-GP) and its cargo variant.
- To compare these outcomes in tumor-free versus tumor-bearing mouse models.
Main Methods:
- Systemic administration of VSV-GP and VSV-GP-[cargo] via intravenous injection.
- Utilized tumor-free and CT26.CL25.IFNAR-/- syngeneic tumor-bearing mouse models.
- Employed molecular pathology techniques, including strand-specific in situ hybridization, to differentiate viral RNA and anti-genome RNA.
Main Results:
- Distinct viral biodistribution and replication patterns were observed between tumor and nontumor sites.
- No significant differences in biodistribution, off-tumor cell tropism, or immune cell responses were found between tumor-free and tumor-bearing models.
- Characterized cellular changes following systemic VSV-GP exposure.
Conclusions:
- The study provides insights into the nonclinical profile of VSV-GP, a potential oncolytic virus therapy.
- Findings support the use of the CT26.CL25.IFNAR-/- model for OV preclinical assessment.
- Demonstrated the utility of advanced molecular pathology methods for OV research.
