Grant: Doctoral Award - Frederick Banting and Charles Best Canada Graduate Scholarships

Systemic delivery of oncolytic viruses is the ideal mode of treatment for metastatic disease because metastatic beds can be dispersed or their extent undiscovered. There are however many barriers to the systemic delivery of oncolytic Vaccinia virus that are presented by the innate and acquired immune systems. Most notably, complement and neutralizing antibody, the latter of which is specifically present in the demographic of patients vaccinated against Smallpox, act together to neutralize the virus and induce activation of the immune system. We have identified that complement and antibody in human blood together can neutralize up to 99% of the virus in vitro. The importance of these clearance mechanisms is then amplified when patients are treated with multiple doses and the amount of antibody produced significantly increases. Additionally, we have discovered that the virus partitioned preferentially to the cellular compartment over the plasma, as demonstrated in vitro as well as in blood samples from patients treated intravenously with oncolytic Vaccinia virus as part of a clinical trial. We have identified that the virus preferentially associates with B cells and phagocytic cells such as neutrophils and monocytes, however the red blood cell compartment also represents an important reservoir of virus due to its size. We are currently evaluating the mouse as a surrogate model for the delivery of oncolytic Vaccinia virus to tumours in the face of all the important clearance mechanisms. Through modeling the interactions between the virus and blood components both in vitro, in vivo, and in samples from previous and upcoming clinical trials, we will identify the interactions that are most important in lowering the effective dose of delivery, and undertake the corollary questions; which mechanisms can we manipulate in order to abrogate neutralization, and which ones can we capitalize on to increase delivery.