Molecular Pathology Methods to Characterize Biodistribution and Pharmacodynamics of the Oncolytic Virus VSV-GP in a Nonclinical Tumor Model.

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.