Mathematical modeling of endogenous and exogenously administered T cell recirculation in mouse and its application to pharmacokinetic studies of cell therapies.

ABSTRACT

Introduction: In vivo T cell migration has been of interest to scientists for the past 60 years. T cell kinetics are important in the understanding of the immune response to infectious agents. More recently, adoptive T cell therapies have proven to be a most promising approach to treating a wide range of diseases, including autoimmune and cancer diseases, whereby the characterization of cellular kinetics represents an important step towards the prediction of therapeutic efficacy. Methods: Here, we developed a physiologically-based pharmacokinetic (PBPK) model that describes endogenous T cell homeostasis and the kinetics of exogenously administered T cells in mouse. Parameter calibration was performed using a nonlinear fixed-effects modeling approach based on published data on T cell kinetics and steady-state levels in different tissues of mice. The Partial Rank Correlation Coefficient (PRCC) method was used to perform a global sensitivity assessment. To estimate the impact of kinetic parameters on exogenously administered T cell dynamics, a local sensitivity analysis was conducted. Results: We simulated the model to analyze cellular kinetics following various T cell doses and frequencies of CCR7+ T cells in the population of infused lymphocytes. The model predicted the effects of T cell numbers and of population composition of infused T cells on the resultant concentration of T cells in various organs. For example, a higher percentage of CCR7+ T cells among exogenously administered T lymphocytes led to an augmented accumulation of T cells in the spleen. The model predicted a linear dependence of T cell dynamics on the dose of adoptively transferred T cells. Discussion: The mathematical model of T cell migration presented here can be integrated into a multi-scale model of the immune system and be used in a preclinical setting for predicting the distribution of genetically modified T lymphocytes in various organs, following adoptive T cell therapies.