在临床中，放射治疗（RT）与免疫检查点阻滞（ICB）或DNA损伤应答途径（DDRi）抑制剂联合应用时，剂量优化以最大化疗效、最小化毒性可能成为一个潜在问题。预临床模型和数学建模可以帮助确定理想的剂量方案，以观察三重治疗的益处。本研究的目的是描述一个数学模型，以捕捉RT与DNA损伤应答途径抑制剂或免疫检查点蛋白-程序性死亡配体1（PD-L1）阻断联合应用的影响。该模型描述了RT介导的抗原呈递细胞的激活如何诱导能够靶向肿瘤细胞的溶解性T细胞的增加，以及联合用药如何通过抑制T细胞耗竭速率来增强免疫反应。该模型使用预临床数据进行拟合，在这些数据中，MC38肿瘤通过RT单独治疗或与抗-PD-L1联合治疗，以及olaparib或ataxia telangiectasia mutated（ATM）抑制剂-AZD0156进行治疗。该模型成功地描述了观察到的数据，并通过视觉预测检查来确认每种治疗方式的内部模型验证的成功性。结果表明，与给定剂量和方案下的DDRi任何额外益处相比，抗-PD-L1在联合RT治疗中的效果在体内达到最大。模型拟合结果表明，相比olaparib，AZD0156是一种更有效的DDRi。替代剂量的模拟结果表明，将抗-PD-L1的功效降低68%可能为ICB与ATM抑制剂联合应用提供证据，并增加三重治疗的相对疗效。© 2023 The Authors. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.

Dosage optimization to maximize efficacy and minimize toxicity is a potential issue when administering radiotherapy (RT) in combination with immune checkpoint blockade (ICB) or inhibitors of the DNA Damage Response Pathway (DDRi) in the clinic. Preclinical models and mathematical modeling can help identify ideal dosage schedules to observe beneficial effects of a tri-therapy. The aim of this study is to describe a mathematical model to capture the impact of RT in combination with inhibitors of the DNA Damage Response Pathway or blockade of the immune checkpoint protein - programmed death ligand 1 (PD-L1). This model describes how RT mediated activation of antigen presenting cells can induce an increase in cytolytic T cells capable of targeting tumor cells, and how combination drugs can potentiate the immune response by inhibiting the rate of T cell exhaustion. The model was fitted using preclinical data, where MC38 tumors were treated in vivo with RT alone or in combination with anti-PD-L1 as well as with either olaparib or the ataxia telangiectasia mutated (ATM) inhibitor-AZD0156. The model successfully described the observed data and goodness-of-fit, using visual predictive checks also confirmed a successful internal model validation for each treatment modality. The results demonstrated that the anti-PD-L1 effect in combination with RT was maximal in vivo and any additional benefit of DDRi at the given dosage and schedule used was undetectable. Model fit results indicated AZD0156 to be a more potent DDRi than olaparib. Simulations of alternative doses indicated that reducing efficacy of anti-PD-L1 by 68% would potentially provide evidence for a benefit of ATM inhibition in combination with ICB and increase the relative efficacy of tri-therapy.© 2023 The Authors. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.