Dose-dependent thresholds of dexamethasone destabilize CAR T-cell treatment efficacy

Abstract

Chimeric antigen receptor (CAR) T-cell therapy is potentially an effective targeted immunotherapy for glioblastoma, 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. Here we present a mathematical model-based analysis of three patient-derived glioblastoma cell lines treated in vitro with CAR T-cells and dexamethasone. Advanced in vitro experimental cell killing assay technologies allow for highly resolved temporal dynamics of tumor cells treated with CAR T-cells and dexamethasone, making this a valuable model system for studying the rich dynamics of nonlinear biological processes with translational applications. We model the system as a nonautonomous, two-species predator-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) dexamethasone destabilizes coexistence equilibria between CAR T-cells and tumor cells in a dose-dependent manner and (2) as dexamethasone is cleared from the system, a stable coexistence equilibrium returns in the form of a Hopf bifurcation. With the model fit to experimental data, we demonstrate that high concentrations of dexamethasone antagonizes CAR T-cell efficacy by exhausting, or reducing the activity of CAR T-cells, and by promoting tumor cell growth. Finally, we identify a critical threshold in the ratio of CAR T-cell death to CAR T-cell proliferation rates that predicts eventual treatment success or failure that may be used to guide the dose and timing of CAR T-cell therapy in the presence of dexamethasone in patients.

Data driven model discovery and interpretation for CAR T-cell killing using sparse identification and latent variables

“…We compared the data first model discovery methodology of SINDy against the CARRGO model, a traditional model first approach originally used to analyze and interpret the CAR T-cell killing dynamics (18, 25). The CARRGO model is defined as, where we have expressed the parameter variables of the CARRGO model in terms of those used in the SINDy model for ease of comparison.…”

“…The data analyzed in this study come from previously conducted experiments whose procedures are described in Sahoo et al (18) and Brummer et al (25), and summarized in Figure 1. The primary brain tumor cell line studied (PBT128) was selected for its endogenous high and relatively uniform expression of IL13R α 2 antigen (89.11% IL13R α 2+) (25). This cell line was derived from glioblastoma tumor resection tissue as described in (44, 45).…”

“…We anticipate similar growth models for the CAR T-cells, 𝒢 y ( y ), with allowance of different models for the different cell types and model constants. Logistic growth is commonly favored for its simplicity in experimental systems (18, 24, 25), while there is growing evidence that Allee effects are required for accurate characterization of low density cancer cell populations (28, 29, 51, 52) or as the result of directed movement (53), the latter of which being an observable feature of CAR T-cell behavior using bright field imaging (18, 25).…”

“…An important example of these is the CAR T-cell Response in GliOma (CARRGO) model, a model that characterizes the in vitro interactions between CAR T-cells and glioma cells (18). The CARRGO model has shed light on the underlying biological mechanisms of action (18, 23), it has informed effective dosing strategies for combination CAR T-cell and targeted radionuclide therapy (24), and CAR T-cell therapy in combination with the anti-inflammatory steroid Dexamethasone (25).…”

Prospective approaches to enhancing CAR T cell therapy for glioblastoma

“…Conversely, low-dose dexamethasone did not reduce CAR T cell antitumor effects in orthotopic xenograft GBM models ( 63 ). By introducing a mathematical model, it was suggested that a critical threshold of CAR T cell death concerning the proliferation rate could guide the dose and timing of CAR T cell delivery in patients administered dexamethasone ( 64 ). Future clinical studies are required to determine the effects of dexamethasone on CAR T therapy.…”