Nalecz Institute of Biocybernetics and Biomedical Engineering, Polish Academy of Sciences, Ks. Trojdena 4, 02-109 Warsaw, Poland.
Department of Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, USA.
Int J Mol Sci. 2018 Oct 29;19(11):3377. doi: 10.3390/ijms19113377.
The synergy of radiation and the immune system is currently receiving significant attention in oncology as numerous studies have shown that cancer irradiation can induce strong anti-tumor immune responses. It remains unclear, however, what are the best radiation fractionation protocols to maximize the therapeutic benefits of this synergy. Here, we present a novel mathematical model that can be used to predict and dissect the complexity of the immune-mediated response at multiple tumor sites after applying focal irradiation and systemic immunotherapy. We successfully calibrate the proposed framework with published experimental data, in which two tumors were grown in mice at two spatially-separated sites from which only one was irradiated using various radiation fractionation protocols with and without concurrent systemic immunotherapy. The proposed model is calibrated to fit the temporal dynamics of tumor volume at both sites and can predict changes in immune infiltration in the non-irradiated tumors. The model was then used to investigate additional radiation fractionation protocols. Model simulations suggest that the optimal radiation doses per fraction to maximize anti-tumor immunity are between 10 and 13 Gy, at least for the experimental setting used for model calibration. This work provides the framework for evaluating radiation fractionation protocols for radiation-induced immune-mediated systemic anti-tumor responses.
辐射与免疫系统的协同作用目前在肿瘤学领域受到广泛关注，因为大量研究表明，癌症放疗可以诱导强烈的抗肿瘤免疫反应。然而，目前尚不清楚哪种放疗分割方案最能最大限度地发挥这种协同作用的治疗益处。在这里，我们提出了一种新的数学模型，可用于预测和剖析在应用焦点照射和全身免疫治疗后，多个肿瘤部位的免疫介导反应的复杂性。我们成功地用发表的实验数据对所提出的框架进行了校准，其中两个肿瘤在两个空间分离的部位生长，只有一个部位接受了不同的放疗分割方案的照射，同时进行了或不进行全身免疫治疗。所提出的模型经过校准以适应两个部位的肿瘤体积的时间动态，并可以预测未照射肿瘤中的免疫浸润变化。然后，该模型用于研究其他放疗分割方案。模型模拟表明，为了最大限度地提高抗肿瘤免疫，每分次的最佳辐射剂量在 10 到 13Gy 之间，至少对于用于模型校准的实验设置是如此。这项工作为评估辐射诱导的免疫介导的全身抗肿瘤反应的放疗分割方案提供了框架。
