PT  - JOURNAL ARTICLE
AU  - David Hodson
AU  - Hitesh Mistry
AU  - James Yates
AU  - Paul Farrington
AU  - Anna Staniszewska
AU  - Sofia Guzzetti
AU  - Michael Davies
AU  - Leon Aarons
AU  - Kayode Ogungbenro
TI  - Radiation in Combination with Immune Checkpoint Blockade and DNA Damage Response Inhibitors in Mice: Dosage Optimisation in MC38 Syngeneic Tumours via Modelling and Simulation
AID  - 10.1124/jpet.122.001572
DP  - 2023 Jan 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - JPET-AR-2022-001572
4099  - http://jpet.aspetjournals.org/content/early/2023/06/22/jpet.122.001572.short
4100  - http://jpet.aspetjournals.org/content/early/2023/06/22/jpet.122.001572.full
AB  - Clinical trials assessing the impact of Radiotherapy (RT) in combination with inhibitors of the DNA Damage Response Pathway (DDRi) and/or immune checkpoint blockade are currently ongoing. However, current methods for optimising 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 tumour immune interactions. The model was fitted to datasets which 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 modelling was performed followed by internal validation with Visual Predictive Checks (VPC). Simulations of alternative dosage regimen and scheduling were performed to identify optimal candidate dosage regimen 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 tumour 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 to ICI in combination with RT. Simulation of alternative dosage regimen indicated that lowering the dosage of ICI to between 2-4mg/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 RT/DDRi/ICI in preclinical tumour models and identify optimal dosage regimens which could be of translational benefit.