Author: Daisuke Kawahara, Yoichi Watanabe 👨🔬
Affiliation: Department of Radiation Oncology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Department of Radiation Oncology, University of Minnesota Medical School 🌍
Purpose: Combination therapies with immunotherapy (IT) and radiotherapy (RT) are widely used, but the optimal IT timing is unclear. This study leverages a computational cellular automaton (CA) model, calibrated with clinical data, to investigate the timing of IT alongside fractionated RT, with the goal of maximizing Tumor Control Probability (TCP).
Methods: A cellular automaton (CA) model was developed to simulate spatial and temporal tumor dynamics in head and neck cancer, calibrated to match clinical TCP data (~20-30%) by adjusting key parameters such as α, β, repair rate, immune activation rate, and clearance rate. The CA model accounted for interactions between tumor proliferation, hypoxia-driven VEGF production, angiogenesis, and immune-mediated cell death. RT (35 fractions of 2 Gy) was simulated to induce tumor cell death and antigen release, priming immune responses. IT effects were modeled as APC-mediated immune activation and effector recruitment, modulated by RT-induced reoxygenation and immunosuppressive factors like TGF-β. The timing of IT initiation was adjusted between 0 and 35 days after RT started to investigate its relationship with TCP.
Results: IT combined with RT significantly improved TCP compared to RT alone, achieving 80-86% when initiated within two weeks of RT start. TCP showed a transient drop when IT began within 6-8 days post-RT, improving between days 9 and 14 due to immune activation. The increase in immune cell activity corresponds to enhanced antigen release due to RT-induced tumor cell death and reoxygenation of the tumor microenvironment. APC activation played a pivotal role in amplifying the immune response, driving subsequent T-cell recruitment and activation.
Conclusion: The highest TCP was achieved when IT was initiated within two weeks of RT start, underscoring the role of RT-induced immune priming and reoxygenation. These findings highlight the potential of computational models to optimize the timing of combination cancer therapies.