Rethinking the seven-day treatment-free interval in T-cell engager therapy using agent-based modeling

The CD3/CD19 bispecific T cell engager (TCE) blinatumomab has shown efficacy in relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL), but response rates are often limited by T cell exhaustion. Recent preclinical studies suggest that incorporating treatment-free intervals (TFIs) into dosing schedules may enhance therapeutic outcomes.

To systematically evaluate alternative TFI strategies, we developed an agent-based model (ABM) of tumor-T cell interactions under various blinatumomab dosing regimens. The model was calibrated using published in vitro data and incorporated spatial, stochastic, and mechanistic rules governing T cell activation, cytotoxicity, proliferation, and exhaustion.

Our ABM recapitulates experimental observations showing that a 7-day TFI improved T cell function over continuous dosing during the initial 28-day treatment period. However, when simulations were extended to a full 42-day cycle to mimic clinical regimen, this advantage was lost. In contrast, shorter TFIs consistently outperformed both 7-day and continuous schedules, leading to superior tumor control at all timepoints. A translationally oriented Monday-through-Friday (MO_FR) regimen also achieved comparable benefits.

Our results indicate that the empirically tested 7-day TFI schedule may not be optimal. TFI with shorter intervals as well as translationally relevant schedules such as MO_FR, may offer greater therapeutic benefit. This work demonstrates the value of ABM in preclinical immunotherapy design and supports model-guided refinement of TCE dosing strategies prior to clinical translation. Future work will focus on validating these predictions in more complex in vivo models and leveraging patient-derived data to guide personalized TCE treatment design.