Seneca Valley Virus, a Systemically Deliverable Oncolytic Picornavirus, and the Treatment of Neuroendocrine Cancers

Abstract

BackgroundNumerous clinical trials have demonstrated that oncolytic viruses can elicit antitumor responses when they are administered directly into localized cancers. However, the treatment of metastatic disease with oncolytic viruses has been challenging due to the inactivation of viruses by components of human blood and/or to inadequate tumor selectivity.MethodsWe determined the cytolytic potential and selectivity of Seneca Valley Virus-001 (SVV-001), a newly discovered native picornavirus, in neuroendocrine and pediatric tumor cell lines and normal cells. Suitability of the virus for intravenous delivery in humans was assessed by blood inactivation assays. Safety was evaluated in vivo using an immune-competent mouse model, and efficacy was evaluated in vivo in athymic mice bearing tumors derived from human small-cell lung cancer and retinoblastoma cell lines.ResultsCell lines derived from small-cell lung cancers and solid pediatric cancers were at least 10000-fold more sensitive to the cytolytic activity of SVV-001 than were any of the adult normal human cells tested. Viral infectivity was not inhibited by human blood components. Intravenous doses up to 1 × 1014 virus particles (vp) per kg were well tolerated, and no dose-limiting toxicity was observed in immune-competent mice. A single intravenous dose of 1 × 108 vp per kg into athymic mice bearing preestablished small-cell lung or retinoblastoma tumors resulted in complete, durable responses in ten of ten and five of eight mice, respectively.ConclusionsSVV-001 has potent cytolytic activity and high selectivity for tumor cell lines having neuroendocrine properties versus adult normal cells. Systemically administered SVV-001 has potential for the treatment of metastatic neuroendocrine cancers.

Gene therapy progress and prospects cancer: oncolytic viruses

“…For example, the porcine Seneca Valley virus has recently been discovered to possess antiGene therapy progress and prospects cancer T-C Liu and D Kirn tumoral activity against certain cancers of neuroendocrine origin. 46 It has been speculated that the tumor selectivity is based on differential receptor binding in cancer and normal cells, but more work needs to be done to verify this and to study the impact of the immune system has on the virus. Myxoma virus, a rabbit virus, has also been assessed as an oncolytic agent.…”

Oncolytic viruses: From bench to bedside with a focus on safety

“…114,115 Serum samples taken from different farm animal populations indicated that (healthy) pigs and other animals are exposed to SVV. However, attempts to infect pigs with SVV isolates failed to demonstrate any specific disease.…”

“…SVV does not infect humans but does propagate in tumor cells with neuroendocrine features, giving the virus a safe profile for use in virotherapy. 114,115 Since its introduction as an oncolytic virus in 2007, SVV has shown preclinical efficacy in nude mice xenograft models for several malignancies. [114][115][116][117][118] In a phase I clinical trial employing an intravenous dose escalation in patients with neuroendocrine tumors, SVV had (marginal) treatment benefits without causing serious adverse events when administered even in high dose (10 11 viral particles/kg).…”

“…114,115 Since its introduction as an oncolytic virus in 2007, SVV has shown preclinical efficacy in nude mice xenograft models for several malignancies. [114][115][116][117][118] In a phase I clinical trial employing an intravenous dose escalation in patients with neuroendocrine tumors, SVV had (marginal) treatment benefits without causing serious adverse events when administered even in high dose (10 11 viral particles/kg). 119 A phase II RCT in patients with extensive stage NSCLC and a phase I dose escalation trial in pediatric patients with neuroblastoma, rhabdomyosarcoma or rare tumors with neuroendocrine features are currently underway.…”

Clinical development directions in oncolytic viral therapy

“…151 It is the representative member of a new genus, Senecavirus. The cytolytic potential of this virus was first examined in neuroendocrine and pediatric tumor cell lines.…”