Quantitative systems pharmacology model of GITR-mediated T cell dynamics in tumor microenvironment.

ABSTRACT

T cell interaction in the tumor microenvironment is a key component of immuno-oncology therapy. Glucocorticoid-induced tumor necrosis factor receptor (TNFR)-related protein (GITR) is expressed on immune cells including regulatory T cells (Tregs) and effector T cells (Teffs). Preclinical data suggest that agonism of GITR in combination with Fc-γ receptor-mediated depletion of Tregs results in increased intratumoral TeffTreg ratio and tumor shrinkage. A novel quantitative systems pharmacology (QSP) model was developed for the murine anti-GITR agonist antibody, DTA-1.mIgG2a, to describe the kinetics of intratumoral Tregs and Teffs in Colon26 and A20 syngeneic mouse tumor models. It adequately captured the time profiles of intratumoral Treg and Teff and serum DTA-1.mIgG2a and soluble GITR concentrations in both mouse models, and described the response differences between the two models. The QSP model provides a quantitative understanding of the trade-off between maximizing Treg depletion versus Teff agonism, and offers insights to optimize drug design and dose regimen.