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

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.

Automated summary

In this study, we used mathematical modeling to investigate the impact of the costimulatory molecule CD28 on the response of CAR T cell populations under different sources of variability. Our findings suggest that CD28-bearing CARs mediate a faster and more consistent population response. We also identified key kinetic parameters that influence cell response time and proposed strategies to improve response time among heterogeneous CAR T cell populations by enhancing the catalytic activity of lymphocyte-specific protein tyrosine kinase.