Spatially fractionated radiotherapy: tumor response modelling including immunomodulation

A mathematical tumor response model has been developed, encompassing the interplay between immune cells and cancer cells initiated by either partial or full tumor irradiation. The iterative four-compartment model employs the linear–quadratic radiation response theory for four cell types: active and inactive cytotoxic T lymphocytes (immune cells, CD8⁺ T cells in particular), viable cancer cells (undamaged and reparable cells) and doomed cells (irreparably damaged cells). The cell compartment interactions are calculated per day, with total tumor volume (TV) as the main quantity of interest. The model was fitted to previously published data on syngeneic xenografts (67NR breast carcinoma and Lewis lung carcinoma; (Markovsky et al 2019 Int. J. Radiat. Oncol. Biol. Phys. 103 697–708)) subjected to single doses of 10 or 15 Gy by 50% (partial) or 100% (full) TV irradiation. The experimental data included effects from anti-CD8⁺ antibodies and immunosuppressive drugs. Using a new optimization method, promising fits were obtained where the lowest and highest root-mean-squared error values were observed for anti-CD8⁺ treatment and unirradiated control data, respectively, for both cell types. Additionally, predictive capabilities of the model were tested by using the estimated model parameters to predict scenarios for higher doses and different TV irradiation fractions. Here, mean relative deviations in the range of 19%–34% from experimental data were found. However, more validation data is needed to conclude on the model's predictive capabilities. In conclusion, the model was found useful in evaluating the impact from partial and full TV irradiation on the immune response and subsequent tumor growth. The model shows potential to support and guide spatially fractionated radiotherapy in future pre-clinical and clinical studies. (paper)