Delicate balances in cancer chemotherapy: modeling immune recruitment and emergence of systemic drug resistance
Tran, Anh Phong
Ali Al-Radhawi, M.
Waxman, David J.
Sontag, Eduardo D.
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Citation (published version)Anh Phong Tran, M. Ali Al-Radhawi, Irina Kareva, Junjie Wu, David J Waxman, Eduardo D Sontag. 2020. "Delicate Balances in Cancer Chemotherapy: Modeling Immune Recruitment and Emergence of Systemic Drug Resistance.." Front Immunol, Volume 11, pp. 1376 - ?. https://doi.org/10.3389/fimmu.2020.01376
Metronomic chemotherapy can drastically enhance immunogenic tumor cell death. However, the mechanisms responsible 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 SCID 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 single fixed set of parameters, adjusted neither for individuals nor for drug schedule, recapitulates experimental data across various drug regimens remarkably well, 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. 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.
RightsCopyright © 2020 Tran, Ali Al-Radhawi, Kareva, Wu, Waxman and Sontag. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.