Optimising radiotherapy and immunotherapy timing: a mechanistic model of the tumour microenvironment

This study aimed to determine the optimal scheduling of radiotherapy (RT) and anti-PD-1/CTLA-4 immune checkpoint inhibitors (ICIs) in a murine model of mesothelioma. BALB/c mice inoculated with a syngeneic mesothelioma tumour on the flank were treated with combination RT and ICI, and tumour growth was measured. An extension of an existing mechanistic model of the tumour microenvironment was fitted to the data, estimating growth, clearing of RT-damaged tumour cells, release of antigens, and activation of T-cells. This model was further extended to investigate the effects of tumour hypoxia on treatment efficacy. Each treatment schedule was analysed to calculate the highest tumour control probability (TCP). Combining ICIs with RT increases the TCP, consistent with other pre- clinical studies. Anti-PD-1 was more effective than anti-CTLA-4 at enhancing tumour control in our model. However, administering anti-PD-1 alone was less effective compared to combined anti-CTLA-4 and anti-PD-1. The TCP was robust to changes in the interval between ICI treatment days and delaying anti-CTLA-4 treatment. However, TCP was sensitive to delays in RT treatment and increases in the interval between RT treatment days. This study supports the synergistic effect between RT and ICIs. Further validation of the model on an external dataset is required before the model can be used to inform optimal treatment scheduling for future human clinical trials.