Hormetic and synergistic effects of cancer treatments revealed by modelling combinations of radio - or chemotherapy with immunotherapy

Abstract

Abstract Background Radio/chemotherapy and immune systems provide examples of hormesis, as tumours can be stimulated (or reduced) at low radio/chemical or antibody doses but inhibited (or stimulated) by high doses. Methods Interactions between effector cells, tumour cells and cytokines with pulsed radio/chemo-immunotherapy were modelled using a pulse differential system. Results Our results show that radio/chemotherapy (dose) response curves (RCRC) and/or immune response curves (IRC) or a combination of both, undergo homeostatic changes or catastrophic shifts revealing hormesis in many parameter regions. Some mixed response curves had multiple humps, posing challenges for interpretation of clinical trials and experimental design, due to a fuzzy region between an hormetic zone and the toxic threshold. Mixed response curves from two parameter bifurcation analyses demonstrated that low-dose radio/chemotherapy and strong immunotherapy counteract side-effects of radio/chemotherapy on effector cells and cytokines and stimulate effects of immunotherapy on tumour growth. The implications for clinical applications were confirmed by good fits to our model of RCRC and IRC data. Conclusions The combination of low-dose radio/chemotherapy and high-dose immunotherapy is very effective for many solid tumours. The net benefit and synergistic effect of combined therapy is conducive to the treatment and inhibition of tumour cells.