429. Optimizing Intratumoral Oncolytic Virus Delivery Using Hemodynamic Manipulations

Abstract

Oncolytic virotherapies like vesicular stomatitis virus (VSV) are experimental cancer therapies wherein naturally evolved or engineered viruses selectively infect tumor cells, inducing tumor cell death (oncolysis), immunotherapeutic responses, and tumor regression. Our mathematical model predicts increasing delivery, distribution, and size of intratumoral infectious centers will increase the probability of achieving tumor cure from direct oncolysis. However, currently intratumoral infection is heterogeneously distributed, resulting in intratumoral infection voids. These voids are predicted to be a result of barriers to intratumoral virus that have the potential to be targeted in order to optimize current oncolytic regimens consistent with mathematical predictions.Optimization requires the ability to accurately visualize and analyze intratumoral infection noninvasively in animals. Here we have used dynamic radiohistology in which noninvasive SPECT/CT imaging after the administration of recombinant virus expressing the sodium-iodide symporter (NIS) reporter gene is used to visualize radiotracer uptake at centers of active NIS expression correlating with intratumoral infectious centers. The SPECT/CT data was analyzed using distributive distance transformation algorithms that quantitatively assess changes in intratumoral distribution and infection voids, allowing for testing of the mathematical model predictions. This technique has proven to be valuable in observing location, size, and evolution of intratumoral infectious centers in three dimensions, and quantitative analysis of infection distribution using SPECT/CT data has the potential to increase understanding of barriers to therapeutic success.Hemodynamic changes are thought to alter tumoral perfusion pressure, a barrier to intratumoral virus delivery. Indeed, we show that increasing intratumoral perfusion pressure through an increase in systemic blood pressure results in an increase in survival matched with an increase in delivery shown using the above analytical methods. Conversely, intratumoral delivery decreases with a decrease in blood pressure. This confirms the ability to use a mathematically guided approach to inform and analyze increases in oncolytic virus therapeutic efficacy and highlights the importance of hemodynamic regulation during therapeutic administration.