CAR T-cell and oncolytic virus dynamics and determinants of combination therapy success for glioblastoma

Abstract

Glioblastoma is a highly aggressive and treatment-resistant primary brain cancer. While chimeric antigen receptor (CAR) T-cell therapy has demonstrated promising results in targeting these tumors, it has not yet been curative. An innovative approach to improve CAR T-cell efficacy is to combine them with other immune modulating therapies. In this study, we investigate in vitro combination of IL-13Rα2 targeted CAR T-cells with an oncolytic virus (OV) and study the complex interplay between tumor cells, CAR T-cells, and OV dynamics with a novel mathematical model. We fit the model to data collected from experiments with each therapy individually and in combination to reveal determinants of therapy synergy and improved efficacy. Our analysis reveals that the virus bursting size is a critical parameter in determining the net tumor infection rate and overall combination treatment efficacy. Moreover, the model predicts that administering the oncolytic virus simultaneously with, or prior to, CAR T-cells could maximize therapeutic efficacy.

Keywords: CAR T-cells; Combination therapies; Glioblastoma; IL-13Rα2; Oncolytic virus; Virus burst size.