Mathematical modelling of the synergistic combination of radiotherapy and indoleamine-2,3-dioxygenase (IDO) inhibitory immunotherapy against glioblastoma

Objective: Recent research has shown that combining radiotherapy and immunotherapy can counteract the ability of cancer to evade and suppress the native immune system. To optimise the synergy of the combined therapies, factors such as radiation dose and fractionation must be considered, alongside numerous parameters resulting from the complexity of cancer-immune system interactions. It is instructive to use mathematical models to tackle this problem. Methods: In this work, we adapted a model primarily to describe the synergistic effect between single-fraction radiotherapy and immunotherapy (1-methyl tryptophan) observed in previous experiments with glioblastoma-carrying rats. We also showed how the model can be used to generate hypotheses on the outcome of other treatment fractionation schemes. Results: The model successfully reproduced the results of the experiments. Moreover, it provided support for the hypothesis that, for a given biologically effective dose, the efficacy of the combination therapy and the synergy between the two therapies are favoured by the administration of radiotherapy in a hypofractionated regime. Furthermore, for a double-fraction irradiation regimen, the synergy is favoured by a short time interval between the treatment fractions. Conclusion: It was concluded that the model could be fitted to reproduce the experimental data well within its uncertainties. It was also demonstrated that the fitted model can be used to form hypotheses to be validated by further pre-clinical experiments. Advances in knowledge: The results of this work support the hypothesis that the synergetic action of combined radiotherapy and immunotherapy is favoured by using a hypofractionated radiation treatment regimen, given over a short time interval.