Enhancing the Delivery of Oncolytic Vaccinia Virus to the Tumors of Hosts with Pre-Existing Immunity

Abstract

Oncolytic viruses (OVs) have begun to show their promise in the clinical setting, however these results have been predominantly associated with loco-regional administration of virus. The treatment of metastatic disease necessitates a systemic approach to virus delivery. The circulatory system, though, is a hostile environment for viruses and the advantages associated with intravenous (IV) delivery come at a heavy cost that must be understood and brokered. Pre-existing immunity, specifically through the function of antibody and complement, poses a significant hurdle to the IV delivery of infectious virus to dispersed tumor beds. This is of particular importance for therapeutic vaccinia viruses as a majority of today’s cancer patients were vaccinated during the smallpox eradication campaign. In vitro neutralization assays of oncolytic vaccinia virus demonstrated that the antibodies elicited from smallpox vaccination, and also the anamnestic response in patients undergoing Pexa-Vec treatment, was minimally neutralizing in the absence of functional complement. Accordingly, in a Fischer rat model, complement depletion stabilized virus in the blood of pre-immunized hosts and correlated with improved delivery to mammary adenocarcinoma tumors. Complement depletion additionally enhanced infection of tumors following direct intratumoral injection of virus. The feasibility and safety of using a complement inhibitor, CP40, was tested in a cynomolgus macaque model. Immune animals saw an average 10-fold increase in infectious virus titer at an early point after the infusion, and a prolongation of the time during which infectious virus was still detectable in the blood. We have also demonstrated that vaccinia virus engages in promiscuous interactions with cells in the blood and that these interactions may be partially complement-dependent. Additionally, we have translated this complement inhibition approach to other OV candidates and found that reovirus, measles virus and a virus pseudo typed with the LCMV glycoprotein all elicit antibodies, that to some degree, are dependent on complement activation to neutralize their target viruses. We show here that capitalizing on the complement dependence of anti-viral antibody with adjunct complement inhibitors may increase the effective dose to enable successful delivery of multiple rounds of OV in immune hosts.