Mathematical Modeling to Simulate the Effect of Adding Radiation Therapy to Immunotherapy and Application to Hepatocellular Carcinoma.
Mathematical Modeling to Simulate the Effect of Adding Radiation Therapy to Immunotherapy and Application to Hepatocellular Carcinoma.
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DOI：
10.1016/j.ijrobp.2021.11.008
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发表时间：
2022-03-15
期刊：
影响因子：
--
通讯作者：
Grassberger C
中科院分区：
文献类型：
--
作者：
Sung W;Hong TS;Poznansky MC;Paganetti H;Grassberger C
目的建立一个模拟免疫检查点抑制剂(ICIS)联合放射治疗(RT)的综合框架，并将其应用于研究ICI-RT联合方案在肝细胞癌(HCC)中的应用。该机制数学模型基于免疫系统和肿瘤之间的动态生物相互作用，使用来自患者血液样本和临床试验结果的输入数据。细胞隔室由常微分方程式描述，代表受辐射和未受辐射的肿瘤细胞和淋巴细胞。ICI的效果是利用免疫激活项模拟的，该免疫激活项基于在1/2期肝癌临床试验中观察到的肿瘤大小变化。模拟联合方案是基于正在进行的ICI-RT试验。建议的框架成功地描述了在肝细胞癌患者接受杜伐单抗治疗的早期临床试验中观察到的肿瘤体积轨迹。对于ICI-RT方案，照射的肿瘤分数是影响疗效的最重要的参数。对于90%的肿瘤细胞被照射，在非照射的肿瘤部位，将RT添加到ICI产生的临床益处从33%增加到71%。该模型与临床数据一致，表明预后与初始肿瘤体积和淋巴细胞计数有关。我们展示了在临床试验设计中预测无进展生存曲线的模型应用，表明显示显著改善的队列大小在很大程度上依赖于受照射的肿瘤分数。我们提出了一个框架，扩展了辐射细胞杀伤模型，以包括循环淋巴细胞和ICIS的影响，并允许模拟组合策略。模拟预测，RT与ICI联合应用的显著好处来自于照射后肿瘤负担的减少和相关的免疫抑制。这方面需要包括在对结果的解释和新的联合试验的设计中。
To develop a comprehensive framework to simulate the response to immune checkpoint inhibitors (ICIs) in combination with radiation therapy (RT) and to apply the framework for investigating ICI-RT combination regimen in patients with hepatocellular carcinoma (HCC). The mechanistic mathematical model is based on dynamic biological interactions between the immune system and the tumor using input data from patient blood samples and outcomes of clinical trials. The cell compartments are described by ordinary differential equations and represent irradiated and nonirradiated tumor cells and lymphocytes. The effect of ICI is modeled using an immune activation term that is based on tumor size changes observed in a phase 1/2 clinical trial for HCC. Simulated combination regimen are based on ongoing ICI-RT trials. The proposed framework successfully describes tumor volume trajectories observed in early-stage clinical trials of durvalumab monotherapy in patients with HCC. For ICI-RT treatment regimen the irradiated tumor fraction is the most important parameter for the efficacy. For 90% of the tumor cells being irradiated, adding RT to ICI yields an increase in clinical benefit from 33% to 71% in nonirradiated tumor sites. The model agrees with clinical data showing an association of outcome with initial tumor volume and lymphocyte counts. We demonstrate model application in clinical trial design to predict progression-free survival curves, showing that the cohort size to show significant improvement heavily depends on the irradiated tumor fraction. We present a framework extending radiation cell kill models to include circulating lymphocytes and the effect of ICIs and enable simulation of combination strategies. The simulations predict that a significant amount of the benefit from RT in combination with ICI stems from the reduction in irradiated tumor burden and associated immune suppression. This aspect needs to be included in the interpretation of outcomes and the design of novel combination trials.
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DOI：
10.1158/1078-0432.ccr-09-0265
发表时间：
2009-09-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
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DOI：
10.1016/j.ijrobp.2019.01.076
发表时间：
2019-09-01
影响因子：
7
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Hong, Theodore S.
影响因子：
64.5
作者：
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DOI：
10.1158/1078-0432.ccr-17-2386
发表时间：
2018-10-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
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作者：
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Gangadhar TC
影响因子：
1.9
作者：
Kirschner, D;Panetta, JC
通讯作者：
Panetta, JC