Cell Population Dynamics Model of CAR T Cell Survival, Cytotoxicity, and Exhaustion
Nicole Piscopo1,2, Christian Capitini3, Krishanu Saha1,2*
1Department of Biomedical Engineering, University of Wisconsin- Madison
2Wisconsin Institute for Discovery, University of Wisconsin-Madison
3.Department of Hematology and Oncology, University of Wisconsin- Madison
Chimeric antigen receptor (CAR) T cells are genetically engineered cells that are in clinical trials to target and kill tumors. The profound success of CAR T-cells in treating hematological malignancies (e.g., leukemia by targeting CD19) has lead many companies to attempt to scale up and manufacture these engineered cell therapies –. Even once companies have devised ways to manufacture these therapies, there must be a specific set of characteristics that will define their product. These characteristics can include the percentage of CAR+ cells, expression levels of the CAR, activation levels of the T-cells prior to implantation, and exhaustion levels of the CAR T-cells. Further, the functional influence of different sources of heterogeneity in CAR T-cells needs to be taken into account. To address these issues, we have developed mathematical models to track CAR T-cell and tumor cell interactions. These differential equation models use inputs such as number of CAR T-cells and their surface density, number of target cells and their antigen density, and presence or lack of T-cell stimulants while predicting the decline in tumor cells number. Results with this model incorporating T-cell exhaustion indicates that defined populations of CAR T-cells with high and low CAR activity can efficiently kill cancer cells while reducing off-target healthy cell toxicity. Model predictions will be of high clinical relevance to better define CAR T-cell mixtures to minimize the amount of off-target cytotoxicity and rate of exhaustion of the CAR T-cells before tumor regression can be achieved.
References:  M. Sadelain et al., Nat. Rev. Cancer, 2003.  G. Welstead et al., Editas Medicine /Juno Therapeutics, 2016.  L. Poirot et al., Cancer Res., 2015.
Funding: NSF EAGER Biomanufacturing CBET-1645123.