Designing and building oncolytic viruses

Maroun, Justin; Muñoz-Alía, Miguel; Ammayappan, Arun; Schulze, Autumn; Peng, Kah-Whye; Russell, Stephen

• • iv delivery IV delivery of an OV seems advantageous in the setting of metastatic disease, allowing the virus to potentially access all sites of disease via the circulation soon after infusion. In a clinical setting, systemic delivery may be preferred since it is more broadly applicable than IT inoculation, regardless of tumor location and total tumor burden. Yet, attempts at systemic delivery have shown limited success; the administered virus is immediately diluted in the circulating blood volume (∼5 l), so extremely high doses are needed to achieve meaningful circulating titers. A clinical trial using an oncolytic pox virus, JX-594, demonstrated that virus could only be detected in tumors of patients that received at least 10 9 p.f.u. per IV dose without any virus being detected in tumors of the lower dose cohorts of patients [62] . Because of this important dilution effect, doses required for IV therapy may have to be up to 1000-fold higher than for IT administration, which results in significant manufacturing challenges as well as a unique set of toxicities [2] . Administration of high titers of virus intravenously can lead to hepatotoxicity, thrombocytopenia and lymphopenia [33, 63] .