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

Abstract

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.

Comparative efficacy and safety of metronomic chemotherapy in breast cancer

“…In addition to the direct inhibition of tumor cells, it also has anti-angiogenesis and immunomodulation effects, [25–27] because of which researchers tend to combine MC with anti-angiogenic or immune therapy. Conventional chemotherapy regiments prescribe long intervals to allow normal cells to recover and limit side effects, however, this may allow cancer cells to regenerate and acquire resistance [28,29] . MC does not rely on powerful killing effect but inhibits tumor by influencing multiple mechanisms such as apoptosis, senescence, non-apoptotic cell death and immunogenic cell death, anti-angiogenesis and immune regulation, and is less likely to develop drug resistance [30,31] .…”

“…Conventional chemotherapy regiments prescribe long intervals to allow normal cells to recover and limit side effects, however, this may allow cancer cells to regenerate and acquire resistance. [28,29] MC does not rely on powerful killing effect but inhibits tumor by influencing multiple mechanisms such as apoptosis, senescence, non-apoptotic cell death and immunogenic cell death, antiangiogenesis and immune regulation, and is less likely to develop drug resistance. [30,31] This may be why MC works better than conventional chemotherapy.…”

A model for the intrinsic limit of cancer therapy: duality of treatment-induced cell death and treatment-induced stemness

“…Druginduced resistance thus poses an intrinsic limit to curability of tumors under any treatment that involves cell stress, as is the case with chemotherapy, target-selected therapy or radiation. The role of somatic Darwinian evolution in recurrence relative to that of non-genetic cell state transitions has been analyzed using mathematical models in order to minimize selection pressure during treatment (4,5,(39)(40)(41). However, the intrinsic limit that induced resistance places on therapy has not been systematically evaluated.…”