Antiangiogenic therapy enhances CAR-T cell efficacy in solid tumors: Insights from a hybrid multiscale model.

BACKGROUND AND

OBJECTIVES

Despite the remarkable success of chimeric antigen receptor (CAR) T cells in hematological malignancies, their therapeutic efficacy in solid tumors is still limited, largely due to the insufficient infiltration of CAR-T cells and the immunosuppressive tumor microenvironment (TME). Recently, murine studies have shown that anti-angiogenic therapy can improve the efficacy of CAR-T cells. However, extensive research is required to unveil the underlying mechanism and develop effective therapeutic protocols.

METHODS

Here, we developed a hybrid discrete - continuous multi-scale computational model to study solid tumor growth, angiogenesis, and CAR-T cell infiltration. Our model considers the intravenous infusion of CAR-T cells, their extravasation through the endothelium, and their cytotoxic effect in the TME. Therefore, this model enables us to robustly investigate the impact of anti-angiogenic therapy on the efficacy of CAR-T cells.

RESULTS

Our findings showed that anti-angiogenic therapy enhances the delivery and efficacy of CAR-T cells in solid tumors. Subsequently, we evaluated different therapeutic regimens. The results revealed that although both adjuvant and neoadjuvant anti-angiogenic therapy can improve outcome, the neoadjuvant regimen yields higher survival rates. Moreover, our model suggested an optimal dosing schedule to maximize survival.

CONCLUSIONS

Our results provide profound insight into the therapeutic dynamics of combined anti-angiogenic and CAR-T cell therapy. Additionally, the model establishes a computational framework for selecting treatment regimens for clinical trials.