基于免疫系统人源化小鼠PDX模型的奥希替尼人体起效剂量预测研究

With the development of molecular precision medicine, the curative effects of osimertinib were more significant than those of the existing chemotherapy drugs and EGFR-TKI standard treatment, as the epidermal growth factor receptor tyrosine-kinase-inhibitors for the treatment of Non-small cell lung cancer, but these medicines had serious adverse reaction. Individual adjustments to the dosage of the drug not only reduce adverse reactions, but also reduce the efficacy. And NSCLC has a long clinical end time, which is not operable as the basis for dose-adjustment. Therefore, we tried to predict the human effective dose of osimertinib in animal models of non-immunogenic tumor and immunogenic tumor, compared with the recommended effective dose in clinical practice ,as a new basis for dose-adjustment. The solution of this project was to establish the patient-derived xenograft model and human hematopoietic stem cell and patient-derived xenograft model in NSG mice, the clinical simulation of which was higher. The clinical trials of different doses of ositinib were simulated on the whole animal level. The change of tumor size, blood concentration, tissue concentration and rate of tumor cell apoptosis were observed. The pharmacokinetic/pharmacodynamic model was established to investigate the correlation between dose, drug concentration, rate of tumor cell apoptosis and drug efficacy and to predict the response concentration of the drug in the human body. The research results of this project can can provide clinical information for the individual administration of osimertinib, and contribute to the rapid search for the effective dose of the drug in human body in the later clinical trials, so as to optimize the clinical dose.

随着分子精确医学的进步，NSCLC的EGFR-TKI药物奥希替尼与已有的化疗药物和EGFR-TKI标准治疗相比，疗效显著，但是其不良反应也很严重。个体化调整其给药剂量，固然可以减少不良反应，但是也会降低疗效。而NSCLC的临床终点时间又比较漫长，作为剂量调整的依据不具备可操作性。因此，我们尝试在冷、热肿瘤动物模型上对奥希替尼的人体起效剂量进行预测并与临床推荐有效剂量比较，作为剂量调整的新依据。本课题的解决思路是建立临床仿真度较高的NSG小鼠PDX模型和Hu-HSC-PDX模型，在动物水平模拟奥希替尼的临床给药试验。获取荷瘤鼠的肿瘤大小、血清/组织药物浓度、肿瘤细胞凋亡率的变化；通过建立PK/PD模型，寻找它们之间的相互关联，预测药物在人体中的起效响应浓度。本课题的研究成果可以为奥希替尼的个体化给药提供有临床参考价值的信息，有助于后期临床试验快速寻找药物的人体起效剂量，从而优化临床给药剂量。

本项目旨在（1）通过建模仿真手段建立起奥希替尼“剂量-浓度-生物标志物—肿瘤细胞凋亡率-肿瘤体积”联系，比较奥希替尼的预测有效浓度（及基于这个浓度所得的预测剂量）与实际临床剂量之间的关系，（2）探讨临床上通过降低剂量来减小奥希替尼不良反应的可行性，以及通过（3）比较基于荷瘤小鼠的人体预测剂量和实际临床剂量，讨论利用荷瘤小鼠评价药物抗肿瘤效能的合理性。项目组成员紧紧围绕上述目标开展研究并基本完成计划研究目标。此外，针对临床上普遍采用的化疗联合分子靶向治疗的现状，我们结合本项目所建立起的奥希替尼PK/PD模型，以奥希替尼联合培美曲塞为例，基于真实的联合治疗药理学机制与序贯影响机理，构建了联合治疗的PK/PD模型，该PK/PD模型在模型结构上具有一定创新性，并从数学层面上阐释了序贯是如何影响奥希替尼与培美曲塞联用的治疗效果。目前项目组已在中文核心期刊发表综述性论文1篇，并计划在1年内发表高质量的研究性与综述性SCI论文各一篇。通过本项目的资助，1名博士研究生与1名硕士研究生获得了系统的科研训练。本项目建立的机制性联合治疗PK/PD模型具有创新与仿真的模型结构，将有助于推动抗肿瘤定量药理发展