Combination therapy of cancer with cancer vaccine and immune checkpoint inhibitors: A mathematical model.
Combination therapy of cancer with cancer vaccine and immune checkpoint inhibitors: A mathematical model.
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DOI：
10.1371/journal.pone.0178479
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Friedman A
中科院分区：
文献类型：
--
作者：
Lai X;Friedman A
在本文中，我们考虑癌症的联合疗法。一种药物是疫苗，它可以激活树突状细胞，从而诱导更多的 T 细胞浸润肿瘤。另一种药物是检查点抑制剂，它使 T 细胞能够保持对抗癌细胞的活性。这两种药物呈正相关，即每种药物剂量的增加都会导致肿瘤体积的减小。我们考虑的问题是，在一定水平下联合使用两种药物进行治疗是否优于单独使用其中一种药物进行“大约”两倍剂量水平的治疗？如果是这样的话，那么我们就说这种剂量组合具有积极的“协同作用”。为了解决这个问题，我们使用偏微分方程组开发了一个数学模型。这些变量包括树突状细胞和癌细胞、CD4+ 和 CD8+ T 细胞、IL-12 和 IL-2、疫苗产生的 GM-CSF 以及与 PD-1 相关的 T 细胞检查点抑制剂。我们使用该模型来探索两种药物单独和组合的功效，并将模拟结果与小鼠实验的数据进行比较。接下来，我们介绍了药物之间协同作用的概念，并开发了一个协同作用图，该图表明了在最大耐受剂量的约束下以什么比例施用药物才能实现最大程度的肿瘤体积缩小。
In this paper we consider a combination therapy of cancer. One drug is a vaccine which activates dendritic cells so that they induce more T cells to infiltrate the tumor. The other drug is a checkpoint inhibitor, which enables the T cells to remain active against the cancer cells. The two drugs are positively correlated in the sense that an increase in the amount of each drug results in a reduction in the tumor volume. We consider the question whether a treatment with combination of the two drugs at certain levels is preferable to a treatment by one of the drugs alone at ‘roughly’ twice the dosage level; if that is the case, then we say that there is a positive ‘synergy’ for this combination of dosages. To address this question, we develop a mathematical model using a system of partial differential equations. The variables include dendritic and cancer cells, CD4+ and CD8+ T cells, IL-12 and IL-2, GM-CSF produced by the vaccine, and a T cell checkpoint inhibitor associated with PD-1. We use the model to explore the efficacy of the two drugs, separately and in combination, and compare the simulations with data from mouse experiments. We next introduce the concept of synergy between the drugs and develop a synergy map which suggests in what proportion to administer the drugs in order to achieve the maximum reduction of tumor volume under the constraint of maximum tolerated dose.