Carrier Cell-based Delivery of an Oncolytic Virus Circumvents Antiviral Immunity

Abstract

Oncolytic viruses capable of tumor-selective replication and cytolysis have shown early promise as cancer therapeutics. However, the host immune system remains a significant obstacle to effective systemic administration of virus in a clinical setting. Here, we demonstrate the severe negative impact of the adaptive immune response on the systemic delivery of oncolytic vesicular stomatitis virus (VSV) in an immune-competent murine tumor model, an effect mediated primarily by the neutralization of injected virions by circulating antibodies. We show that this obstacle can be overcome by administering virus within carrier cells that conceal viral antigen during delivery. Infected cells were delivered to tumor beds and released virus to infect malignant cells while sparing normal tissues. Repeated administration of VSV in carrier cells to animals bearing metastatic tumors greatly improved therapeutic efficacy when compared with naked virion injection. Whole-body molecular imaging revealed that carrier cells derived from solid tumors accumulate primarily in the lungs following intravenous injection, whereas leukemic carriers disseminate extensively throughout the body. Furthermore, xenogeneic cells were equally effective at delivering virus as syngeneic cells. These findings emphasize the importance of establishing cell-based delivery platforms in order to maximize the efficacy of oncolytic therapeutics.

Potential of tumour cells for delivering oncolytic viruses

“…5 Finally, OVs harboured by carrier cells remain at least partly protected from inactivation by the host until released at their destination. 6 In the present review, emphasis will be placed on tumour cell carriers, while the use of mesenchymal, endothelial or bone marrow progenitor cells with different OV systems will be addressed elsewhere in this issue.…”

“…It is worth mentioning in this respect that anti-viral T-cell immunity does not prevent carrier-delivered OVs from infecting target cells. 6 The first step in this protocol is likely to have a lesser impact if the patient has developed immunity against a chosen OV prior to treatment, either naturally (against adenoviruses, for example) or as part of a regular vaccination schedule (as in the case of the measles virus).…”

“…On the other hand, cells derived from haematological malignancies are likely to be suitable for transferring OV to certain disseminated cancers, because they retain some of the features of their untransformed counterparts. 6,27 For instance, the observation that monocytes play a role in transport of the measles virus during natural infection has led to the successful use of corresponding cell lines as carriers for this virus. 27 Established cell lines derived from promonocytic leukaemias are another example.…”

“…47 In other OV/tumour systems, virus delivered by carrier cells was found to avoid seroneutralization partially or totally in actively or passively immunized animals. 6,39 Thus, carrier cell-mediated delivery has a potential to shield input virions against neutralizing antibodies in vivo, but the level of protection appears to depend on the OV/carrier cell pair, the target tumour, the therapeutic protocol (notably treatment repetition, antibody titres). Accordingly, the impact of these parameters should be assessed in immunocompetent animal models where the OV induces a potent neutralizing response.…”

“…Accordingly, the impact of these parameters should be assessed in immunocompetent animal models where the OV induces a potent neutralizing response. 5,6 Furthermore, the use of carrier cells might be combined with other means aimed at taming anti-viral reactions. For example, applying carriers together with plasmapheresis might be a more physiological means of taming anti-viral immune reactions than drug-induced immunosuppression.…”