Radiation in Combination with Immune Checkpoint Blockade and DNA Damage Response Inhibitors in Mice: Dosage Optimization in MC38 Syngeneic Tumors via Modelling and Simulation.

Clinical trials assessing the impact of radiotherapy (RT) in combination with DNA damage response pathway inhibitors (DDRis) and/or immune checkpoint blockade are currently ongoing. However, current methods for optimizing dosage and schedule are limited. A mathematical model was developed to capture the impacts of RT in combination with DDRi and/or anti-PD-L1 [immune checkpoint inhibitor (ICI)] on tumor immune interactions in the MC38 syngeneic tumor model. The model was fitted to datasets that assessed the impact of RT in combination with the DNA protein kinase inhibitor (DNAPKi) AZD7648. The model was further fitted to datasets from studies that were used to assess both RT/ICI combinations as well as RT/ICI combinations followed by concurrent administration of the poly ADP ribose polymerase inhibitor (PARPi) olaparib. Nonlinear mixed-effects modeling was performed followed by internal validation with visual predictive checks (VPC). Simulations of alternative dosage regimens and scheduling were performed to identify optimal candidate dosage regimens of RT/DNAPKi and RT/PARPi/ICI. Model fits and VPCs confirmed a successful internal validation for both datasets and demonstrated very small differences in the median, lower, and upper percentile values of tumor diameters between RT/ICI and RT/PARPi/ICI, which indicated that the triple combination of RT/PARPi/ICI at the given dosage and schedule does not provide additional benefit compared with ICI in combination with RT. Simulation of alternative dosage regimens indicated that lowering the dosage of ICI to between 2 and 4 mg/kg could induce similar benefits to the full dosage regimen, which could be of translational benefit. SIGNIFICANCE STATEMENT: This work provides a mixed-effects model framework to quantify the effects of combination radiotherapy/DNA damage response pathway inhibitors/immune checkpoint inhibitors in preclinical tumor models and identify optimal dosage regimens, which could be of translational benefit.