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

Abstract

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 who achieved a complete response. Using these cases, we constructed virtual scenarios to investigate how variations in baseline tumour and healthy B-cell populations, along with patient-specific factors related to CAR-T cell expansion and B-cell influx from the bone marrow, affect treatment outcomes. Our results suggest that the onset and duration of BCA is 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. Statement of significanceThis study presents a significant advancement in understanding the dynamics of CAR-T cell immunotherapy in B-cell malignancies by introducing a mathematical model that captures the complex interactions between CAR-T cells, tumour cells, and healthy B cells. The model provides crucial insights into how patient-specific factors, such as baseline tumour burden, B-cell populations, and CAR-T cell expansion, influence treatment outcomes, including the onset and duration of B-cell aplasia (BCA), a key marker of therapeutic success. Healthy B cells can act as allies, adversaries, or have a neutral effect on the therapy, depending on the tumour burden. These findings highlight the importance of personalised approaches in CAR-T cell immunotherapy, offering potential pathways to optimise treatment strategies for improved efficacy and patient outcomes.