Mathematical model suggests current CAR-macrophage dosage is efficient to low pre-infusion tumour burden but refractory to high tumour burden

Abstract

Chimeric antigen receptor (CAR)-macrophage therapy is a promising approach for tumour treatment due to antigen-specific phagocytosis and tumour clearance. However, the precise impact of tumour burden, dose and dosing regimens on therapeutic outcomes remains poorly understood. We developed ordinary differential equation (ODE) mathematical modelling and utilised parameter inference to analyse in vitro FACS-based phagocytosis assay data testing CD19-positive Raji tumour cell against CAR-macrophage, and revealed that phagocytosing efficiency of CAR-macrophage increases but saturates as both Raji cell and CAR-macrophage concentrations increase. This interaction resulted in bistable Raji cell kinetics; specifically, within a particular range of CAR-macrophage concentration, low tumour burdens are effectively inhibited, while high tumour burdens remain refractory. Furthermore, our model predicted that CAR-macrophage dosages typically suggested by current clinical trials yield favourable therapeutic outcomes only when tumour burden is low. For split CAR-macrophage infusion with fixed total dosage, the first infusion with high CAR-macrophage dose delivers superior treatment outcomes. Finally, we identified alternative infusion regimens: five billion cells administered monthly for three months, or seven billion cells every two months for six months, can efficiently suppress Raji cell replication irrespective of tumour burden. Our findings highlight CAR-macrophage therapeutic outcomes are strongly influenced by both tumour burden and different dosing regimens. This work underscores that reducing tumour burden, increasing CAR-macrophage dose in the first infusion and prolonging CAR-macrophage persistence are key strategies for achieving durable responses.