Understanding the Interplay of CAR-NK Cells and Triple-Negative Breast Cancer: Insights from Computational Modeling.

ABSTRACT

Chimeric antigen receptor (CAR)-engineered natural killer (NK) cells have recently emerged as a promising and safe alternative to CAR-T cells for targeting solid tumors. In the case of triple-negative breast cancer (TNBC), traditional cancer treatments and common immunotherapies have shown limited effectiveness. However, CAR-NK cells have been successfully employed to target epidermal growth factor receptor (EGFR) on TNBC cells, thereby enhancing the efficacy of immunotherapy. The effectiveness of CAR-NK-based immunotherapy is influenced by various factors, including the vaccination dose, vaccination pattern, and tumor immunosuppressive factors in the microenvironment. To gain insights into the dynamics and effects of CAR-NK-based immunotherapy, we propose a computational model based on experimental data and immunological theories. This model integrates an individual-based model that describes the interplay between the tumor and the immune system, along with an ordinary differential equation model that captures the variation of inflammatory cytokines. Computational results obtained from the proposed model shed light on the conditions necessary for initiating an effective anti-tumor response. Furthermore, global sensitivity analysis highlights the issue of low persistence of CAR-NK cells in vivo, which poses a significant challenge for the successful clinical application of these cells. Leveraging the model, we identify the optimal vaccination time, vaccination dose, and time interval between injections for maximizing therapeutic outcomes.