Exploring the impact of intratumoral heterogeneity on oncolytic virotherapy using agent-based modelling

Oncolytic viruses (OV) are an exciting immunotherapeutic modality currently being investigated for the treatment of glioblastoma multiforme (GBM), an aggressive brain cancer with a poor clinical prognosis. Unfortunately, promising pre-clinical investigations of immunotherapies have led to a number of disappointing trail results. It is clear that recapitulating the tumour microenvironment (TME) and finding useful pre-clinical models to elucidate the efficacy of OVs is crucial to improve OV treatments. CANscript is an ex vivo tumour spheroid model that has been used to improve pre-clinical evaluation as it recapitulates native, patient autologous TME. Leveraging pre-clinical GBM spheroids, we evaluated the infiltration of a herpes simplex OV in patient GBM samples, and constructed a computational representation of this system in PhysiCell, an open-source cell-based simulator, to determine OV characteristics that optimized therapeutic efficacy with respect to the impact of stromal density on OV infiltration. Additionally, we examined how intratumoural heterogeneity in the uptake rate of the OV influences efficacy. Overall, our results showed that the intracellular viral replication rate is the primary driver of OV infiltration patterns observed in the ex vivo samples. This work, therefore, has implications on the development of OVs for the treatment of GBM and in our understanding of the impact of spatial heterogeneity on new treatment approaches.