In silico assessment of CAR macrophages activity against SARS-CoV-2 infection

Macrophage engineering with chimeric antigen receptor is a promising technique first applied to the treatment of tumours and recently suggested as a possible immunotherapeutic route against the COVID-19 disease. Four immunotherapies based on engineered macrophages have been tested in vitro revealing promising, with one of them acting without increasing the cytokines level. We present a mathematical model aimed at the evaluation of both the SARS-CoV-2 virions dynamics and the cytokines production induced, while such newly developed constructs interact with the immune system once administered. The importance of the study lies both in monitoring the dynamics of the infection and in evaluating the cytokine production, since clinical studies show that in critical COVID-19 patients an abnormal cytokines production occurs, a concern to be accounted for in designing appropriate therapeutic strategies. The mathematical model was built in the context of the continuum approach of the mass conservation, while the numerical simulations have been performed introducing parameters deduced from the experiments, using the finite element method. The model simulations allow to analyse and to compare the immune mechanisms underlying the virus dynamics, deepening the investigation for two selected immunotherapies, suggesting that a synergistic work of involved cytokines with phagocytic activity of macrophages occurs. The best SARS-CoV-2 clearance relies not only on the phagocytic capacity of the engineered macrophages, but also on the production of T-lymphocytes, pro- and anti-inflammatory cytokines which in the two cases examined in depth can decrease by 99.7 %, 99.6 % and 69 % respectively, passing from the most effective immunotherapy to the least effective one. This study is the first mathematical model that analyses the dynamics of macrophages engineered to fight the COVID-19, and paves the way for their possible exploitation against such a challenging disease, going beyond existing models involving other immune cells.