Three-Compartment Model of CAR T-cell Immunotherapy

Abstract

Immunotherapy has gained great momentum with chimeric antigen receptor T-cell (CAR T) therapy, in which patients T lymphocytes are genetically manipulated to recognize tumor-specific antigens to increase tumor elimination efficiency. Improved CAR T cell immunotherapy requires a better understanding of the interplay between CAR T cell doses and tumor burden, administration protocol, toxicity, resistance to immunotherapy, among other features. We developed a three-compartment mathematical model to describe tumor response to CAR T cell immunotherapy in immunodeficient mouse models. It encompasses interactions between tumor cells, effector and long-term memory CAR T cells such as tumor induced immunosuppression effects, conversion of memory T cells into effector T cells in the presence of tumor cells, and individual specificities considered as uncertainties in the parameters of the model. The model was able to represent two different immunotherapy scenarios with different CAR receptors and tumor targets reported in the literature. Further in silico studies considering different dosing quantities and tumor burden showed that the proposed model can represent the three possible therapy outcomes: tumor elimination, equilibrium, and escape. We found that therapy effectiveness may also depend on small variations in the parameter values, regarded as intrinsic individual specificities, as T cell proliferation capacity, as well as immunosuppressive tumor microenvironment factors. These issues may significantly reduce the chance of tumor elimination. In this way, the developed model provides potential use for assessing different CAR T cell protocols and associated efficacy without further in vivo experiments.