Safety Studies on Intravenous Administration of Oncolytic Recombinant Vesicular Stomatitis Virus in Purpose-Bred Beagle Dogs

Abstract

VSV-IFNβ-NIS is a novel recombinant oncolytic vesicular stomatitis virus (VSV) with documented efficacy and safety in preclinical murine models of cancer. To facilitate clinical translation of this promising oncolytic therapy in patients with disseminated cancer, we are utilizing a comparative oncology approach to gather data describing the safety and efficacy of systemic VSV-IFNβ-NIS administration in dogs with naturally occurring cancer. In support of this, we executed a dose-escalation study in purpose-bred dogs to determine the maximum tolerated dose (MTD) of systemic VSV-hIFNβ-NIS, characterize the adverse event profile, and describe routes and duration of viral shedding in healthy, immune-competent dogs. The data indicate that an intravenous dose of 10(10) TCID50 is well tolerated in dogs. Expected adverse events were mild to moderate fever, self-limiting nausea and vomiting, lymphopenia, and oral mucosal lesions. Unexpected adverse events included prolongation of partial thromboplastin time, development of bacterial urinary tract infection, and scrotal dermatitis, and in one dog receiving 10(11) TCID50 (10 × the MTD), the development of severe hepatotoxicity and symptoms of shock leading to euthanasia. Viral shedding data indicate that detectable viral genome in blood diminishes rapidly with anti-VSV neutralizing antibodies detectable in blood as early as day 5 postintravenous virus administration. While low levels of viral genome copies were detectable in plasma, urine, and buccal swabs of dogs treated at the MTD, no infectious virus was detectable in plasma, urine, or buccal swabs at any of the doses tested. These studies confirm that VSV can be safely administered systemically in dogs, justifying the use of oncolytic VSV as a novel therapy for the treatment of canine cancer.

Recent advances in vesicular stomatitis virus-based oncolytic virotherapy: a 5-year update

“…Using VSVs encoding type I and type III IFNs Several recent pre-clinical studies have shown that VSVIFNb and VSV-IFNb-NIS (additionally expresses the NIS to track virus spread) are oncoselective and safe in a variety of tumour and animal models [24,[27][28][29][30][31]. Although mice and rats continue to serve as the most commonly used animal models for VSV-based OV therapy, a recent study evaluated the safety of intravenously administered VSV-IFNb-NIS in purpose-bred beagle dogs.…”

“…dose of 10 10 TCID50 was well-tolerated by dogs. Furthermore, no infectious virus was detectable in plasma, urine or buccal swabs at any tested doses [29]. Importantly, VSV-IFNb-NIS is currently in several phase I clinical trials in the USA: against refractory solid tumours (see details at ClinicalTrials.gov trial NCT02923466), stage IV or recurrent endometrial cancer (trial NCT03120624), and relapsed or refractory multiple myeloma, acute myeloid leukemia or T-cell lymphoma (trial NCT03017820).…”

Safety Studies in Tumor and Non-Tumor-Bearing Mice in Support of Clinical Trials Using Oncolytic VSV-IFNβ-NIS

“…Safety studies in research beagles before the start of the canine trial indicated that the maximal tolerated dose (MTD) in dogs is 10 10 TCID 50 (50% tissue culture infective dose) of VSV-hIFNb-NIS or VSVcIFNb-NIS. 6 At 10 · MTD (10 11 TCID 50 ), the doselimiting toxicity is severe hepatotoxicity with elevations in transaminases and prolongation of partial thromboplastin time (PTT), requiring euthanasia of the animal. Intensive pharmacokinetics studies showed a rapid increase in VSV-nucleocapsid (N) RNA in the blood from 10 min to 3 hr after virus infusion (end of acute-phase monitoring).…”

Robust Oncolytic Virotherapy Induces Tumor Lysis Syndrome and Associated Toxicities in the MPC-11 Plasmacytoma Model

“…Additionally, the virus has been administered intravenously to purpose bred research hounds where the maximal tolerated dose was determined to be 10 10 TCID 50 (dose-limiting toxicity was mildly elevated transaminases). 15 VSV-IFNβ-NIS is active against a broad spectrum of tumors of differing tissue origins and tumor response is typically not associated with significant toxicities. For example, in immunocompetent mice with large subcutaneous 5TGM1 myeloma tumors, an intravenous dose of 3 × 10 8 TCID 50 VSV-murine IFNβ-NIS can result in sustained complete remission and induction of tumorspecific memory T cells that protect the mice from new tumor cell challenge.…”