Destabilization of CAR T-cell treatment efficacy in the presence of dexamethasone

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Alexander Brummer

Department of Computational and Quantitative Medicine, Division of Mathematical Oncology, Beckman Research Institute, City of Hope National Medical Center
"Destabilization of CAR T-cell treatment efficacy in the presence of dexamethasone"
CAR T-cell therapy has proven to be a highly effective targeted immunotherapy for glioblastoma multiforme. Yet, there is presently little known about the efficacy of CAR T-cell treatment when combined with the widely used anti-inflammatory and immunosuppressant glucocorticoid Dexamethasone. We present an analysis of glioblastoma organoid cell lines treated along gradients of CAR T-cell therapy and Dexamethasone. We demonstrate that Dexamethasone antagonizes CAR T-cell efficacy, and promotes tumor growth and recurrence. Advanced experimental technologies allow for highly resolved temporal dynamics of in vitro studies of combination therapies of CAR T-cell and Dexamethone, making this a valuable model system for studying the rich dynamics of nonlinear biological processes with translational applications. We model the system as a non-autonomous, two-species, type I, predatory-prey interaction of tumor cells and CAR T-cells, with explicit time-dependence in the clearance rate of Dexamethasone. Using time as a bifurcation parameter, we show that (1) the presence of Dexamethasone destabilizes coexistence equilibria between CAR T-cells and tumor cells and (2) as Dexamethasone is cleared from the system, a stable coexistence equilibrium returns in the form of a Hopf bifurcation.

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