Opportunities to debottleneck the downstream processing of the oncolytic measles virus

Oncolytic viruses (including measles virus) offer an alternative approach to reduce the high mortality rate of late-stage cancer. Several measles virus strains infect and lyse cancer cells efficiently, but the broad application of this therapeutic concept is hindered by the large number of infectious particles required (10(8)-10(12) TCID50 per dose). The manufacturing process must, therefore, achieve high titers of oncolytic measles virus (OMV) during upstream production and ensure that the virus product is not damaged during purification by applying appropriate downstream processing (DSP) unit operations. DSP is currently a production bottleneck because there are no specific platforms for OMV. Infectious OMV must be recovered as intact, enveloped particles, and host cell proteins and DNA must be reduced to acceptable levels to meet regulatory guidelines that were developed for virus-based vaccines and gene therapy vectors. Handling such high viral titers and process volumes is technologically challenging and expensive. This review considers the state of the art in OMV purification and looks at promising DSP technologies. We discuss here the purification of other enveloped viruses where such technologies could also be applied to OMV. The development of DSP technologies tailored for enveloped viruses is necessary to produce sufficient titers for virotherapy, which could offer hope to millions of patients suffering from incurable cancer.