Healthy B cells: Allies or adversaries of CAR-T cell immunotherapy?

Chimeric antigen receptor (CAR)-T cell immunotherapy has achieved significant success against various haematological cancers, including B-cell malignancies. Its efficacy against B-cell cancers is influenced by the presence of healthy B cells expressing the target antigen, and B-cell aplasia (BCA) serves as an indicator of successful therapy outcome. However, the precise influence of healthy B cells on the in vivo dynamics of CAR-T cells and their ultimate impact on therapy outcomes remain unclear. Here, we propose a mathematical model to describe CAR-T cell immunotherapy in B-cell cancer patients. Our model successfully captured the interactions between different CAR-T cell phenotypes, tumour cells, and healthy B cells in patients exhibiting complete clinical responses. Due to typical uncertainties associated with the initial baseline tumour and healthy B-cell populations, we conduct in silico tests by varying these initial quantities to evaluate their potential influence on treatment outcomes. The influence of the initial target-antigen load composition is evident in the dynamic behaviour of biological mechanisms, including competition between target-antigen-expressing populations, the effector-to-target ratio, and immunosuppression. Furthermore, our results suggest that the onset and duration of BCA constitute a patient-specific feature that depends primarily on the continuous influx of newly generated B cells, their proliferative capacity, and the expansion and cytotoxicity of CAR-T cells.