Modelling predicts differences in chimeric antigen receptor T-cell signalling due to biological variability

Abstract

In recent decades, chimeric antigen receptors (CARs) have been successfully used to generate engineered T cells capable of recognizing and eliminating cancer cells. The structure of CARs typically includes costimulatory domains, which enhance the T-cell response upon antigen encounter. However, it is not fully known how those co-stimulatory domains influence cell activation in the presence of biological variability. In this work, we used mathematical modelling to elucidate how the inclusion of one such costimulatory molecule, CD28, impacts the response of a population of CAR T cells under different sources of variability. Particularly, we demonstrate that CD28-bearing CARs mediate a faster and more consistent population response under both target antigen variability and kinetic rate variability. Next, we identify kinetic parameters that have the most impact on cell response time. Finally, based on our findings, we propose that enhancing the catalytic activity of lymphocyte-specific protein tyrosine kinase can result in drastically reduced and more consistent response times among heterogeneous CAR T-cell populations.