Delicate balances in cancer chemotherapy: modeling immune recruitment and emergence of systemic drug resistance

Metronomic chemotherapy can drastically enhance immunogenic tumor cell death. However, the responsible mechanisms are still incompletely understood. Here, we develop a mathematical model to elucidate the underlying complex interactions between tumor growth, immune system activation, and therapy-mediated immunogenic cell death. Our model is conceptually simple, yet it provides a surprisingly excellent fit to empirical data obtained from a GL261 mouse glioma model treated with cyclophosphamide on a metronomic schedule. The model includes terms representing immune recruitment as well as the emergence of drug resistance during prolonged metronomic treatments. Strikingly, a fixed set of parameters, not adjusted for individuals nor for drug schedule, excellently recapitulates experimental data across various drug regimens, including treatments administered at intervals ranging from 6 to 12 days. Additionally, the model predicts peak immune activation times, rediscovering experimental data that had not been used in parameter fitting or in model construction. The validated model was then used to make predictions about expected tumor-immune dynamics for novel drug administration schedules. Notably, the validated model suggests that immunostimulatory and immunosuppressive intermediates are responsible for the observed phenomena of resistance and immune cell recruitment, and thus for variation of responses with respect to different schedules of drug administration.