A pharmacokinetic/pharmacodynamic model predicts tumor debulking improves CAR T-cell efficacy in Large B-Cell Lymphoma

Abstract Chimeric Antigen Receptor (CAR) T-cells produce durable remissions in some large B-cell lymphoma patients, but outcomes are poor in patients with large tumor burdens or limited CAR T-cell expansion. To understand these relationships and explore potential interventions, we applied established population-pharmacokinetic/pharmacodynamic principles to model kinetics of axicabtagene ciloleucel (axi-cel) concentrations and tumor responses to axi-cel, and validated model outputs using independent cohorts. This mechanistic model reproduces and explains poor outcomes associated with high tumor burden and low CAR T-cell expansion, finding that proliferation of large lymphoma populations can outpace the cytotoxic effect of CAR T-cells. A high ratio of lymphoma cells to CAR T-cells is effectively a mechanism of CAR T-cell resistance, which could be modified by tumor debulking before infusion. This model predicts that reducing tumor burden before CAR T-cell infusion may improve durable remission rate. Future clinical studies optimizing bridging therapy may therefore enhance CAR T-cell therapies’ success.