70. Safety, Toxicity and Efficacy of Systemic Recombinant VSV Therapy in Pet Dogs With Spontaneous Cancer

Clinical translation of oncolytic therapy to benefit cancer patients is dependent upon extensive evaluation of viral safety, toxicity and therapeutic efficacy in disease bearing animals. Comparative oncology, the study of naturally occurring cancer in animals, allows evaluation of novel cancer therapies in pet dogs that are similar in size, genetic make-up, physiology and exposure to environmental risk factors to humans. We have previously shown single shot systemic therapy with recombinant Vesicular stomatitis virus (VSV) engineered to express Interferon-beta (IFN) and the sodium-iodide symporter (NIS) in tumor bearing mice results in tumor-specific virus replication that can be monitored noninvasively by SPECT/CT imaging using NIS specific radio-tracer, induces tumor remission and confers significant survival benefit. A comparative oncology approach was utilized to investigate safety, clinical toxicities and therapeutic efficacy of systemic VSV therapy in dogs with spontaneous cancer. A pre-clinical rapid dose-escalation study was performed in healthy lab beagles defined a safe systemic dose range. We initiated evaluation of systemic VSV administration in dogs with spontaneous cancer. 8 dogs with various cancers were treated with VSV expressing either human or canine IFN-beta and NIS. We demonstrate that systemic VSV therapy at a dose of 10(10) TCID is well tolerated in dogs with spontaneous disease. We detected transient hepatotoxicity that resolved spontaneously in 2/8 dogs following systemic VSV-IFN-NIS treatment. No infectious virus was detected in urine or buccal swab samples. Monitoring of disease response indicated that 2/2 dogs with T-cell lymphoma had dramatic disease remission following systemic VSV-hIFN-NIS treatment resulting in partial response, though remission was transient and disease eventually relapsed. Virus pharmacokinetics (PK) studies indicate that dogs with robust responses also had highest viral PK in blood, suggesting therapeutic response is PK dependent. A dose optimization protocol was adopted where gradual dose escalation and multi-dosing protocols are being evaluated. Initial findings indicate two-dose systemic VSV-IFN-NIS therapy in a dog with metastatic Osteosarcoma (OSA) is well tolerated, delays viral decay in blood, and has resulted in improved health of the treated dog with no major disease progression to date. RNAseq analysis of tumor biopsies from treated animals reveals changes in tumor gene expression following systemic VSV therapy. Overall the data demonstrate that recombinant VSV can be safely administered systemically in cancer bearing dogs. Our data suggest that therapeutic response is PK dependent, prompting dose optimization studies that will directly inform and support planned clinical studies to evaluate systemic VSV therapy in patients with relapsed or metastatic cancer.