Quantitative Systems Pharmacology Model Predicts Enhanced Antitumor Efficacy of Combined Cytotoxic T-Lymphocyte-Associated Protein 4 (CTLA-4) and Programmed Cell Death Protein 1 (PD-1) Blockade in a Syngeneic Mouse Model of Breast Cancer
Pharmacology modeling study demonstrates synergistic antitumor efficacy of dual PD-1 and CTLA-4 blockade in mice, indicating key drivers of response.
Key Points
To develop and calibrate a preclinical quantitative systems pharmacology model of anti-PD-1 and anti-CTLA-4 therapies to explain treatment response heterogeneity and evaluate combinatorial synergy.
Constructed a preclinical quantitative systems pharmacology model calibrated jointly against tumor growth data from syngeneic breast cancer mouse models across vehicle, monotherapy, and combination arms.
Simulated a virtual cohort of 500 mice to analyze mechanisms of action, reciprocal synergy, and interindividual response variability.
The model captured tumor growth inhibition across all four treatment arms, driven by anti-PD-1 reinvigorating effector T cells and anti-CTLA-4 depleting regulatory T cells via Fc-dependent antibody-dependent cellular cytotoxicity.
Combined treatment demonstrated an approximate 4-fold reciprocal potency synergy compared with monotherapies.
Virtual cohort simulations revealed that the balance between IL-2-driven CD4+ and CD8+ T-cell expansion, alongside intrinsic tumor growth rates, primarily governed treatment response heterogeneity.