肿瘤细胞治疗研究
英文原题：In silico analysis of a novel protein in CAR T- cell therapy for the treatment of hematologic cancer through molecular modelling, docking, and dynamics approach.
CD19 CAR T 细胞疗法是首个获临床批准的淋巴瘤疗法，在 B 细胞淋巴细胞白血病完全缓解方面取得了高达 90% 的显著结果。
细胞治疗已成为治疗血液系统恶性肿瘤的重要工具。CAR-T 细胞是一种先进细胞疗法，诺华的KYMRIAH和吉利德/Kite Pharma的YESCARTA于2017年获美国食品药品监督管理局（FDA）批准。嵌合受体由细胞外抗原识别位点以及共刺激和信号结构域组成，是T细胞上极其强效的受体之一，可依据抗原标志物靶向特定癌细胞。CD19 CAR-T是首个获批用于淋巴瘤的临床疗法，治疗B细胞淋巴母细胞白血病的完全缓解率最高可达90%。CAR-T治疗B-ALL的高效性，支持将其研究和应用拓展至各类致命性血液系统恶性肿瘤。嵌合受体疗法的关键环节，是设计并构建针对特定癌症的人工受体。因此，在开始体外实验和临床试验之前，使用计算机模拟方法评估工程化嵌合受体的完整性和有效性是适当的选择。本计算机研究可预测嵌合蛋白的分子机制及其与两个配体的相互作用。研究对嵌合蛋白进行了定性分析（结构、蛋白质建模和生理特性）及功能分析（抗原性、致敏性、受体-配体结合能力及信号通路参与情况）。此外，研究通过水相环境下持续100 ns的复合物分子动力学模拟，检验其与受体结合模式的可靠性。模拟结果显示，与CD20相比，CD30更适合作为靶标，其结合能评分更优、结合构象更稳定。
Cellular therapy has emerged as a key tool in the treatment of hematological malignancies. An advanced cell therapy known as chimeric antigen receptor T cell therapy (CAR T-cell therapy) has been approved by the United States Food and Drug Administration (FDA) as KYMRIAH by Novartis and YESCARTA by Gilead/Kite pharma in the year 2017. A chimeric receptor is composed of an extracellular antigen recognition site along with some co-stimulating and signalling domains. On the whole, it turns out to be one of the most potent receptors on T cells targeting a specific type of cancer cell based on its antigenic marker. CD19 CAR T-cell therapy is the first clinically approved therapy for lymphoma with remarkable results in complete remission of B cell lymphoblastic leukemia up to 90%. The high rate of effectiveness of the CAR T-cell therapy against B-ALL justifies the investigation and application of this therapy for fatal diseases like all types of hematological malignancies. The most critical aspect of chimeric receptor therapy is designing and building an artificial receptor that is specific to a given type of cancer. For this reason, the in silico technique is an appropriate model to investigate the integrity and effectiveness of the engineered chimeric receptor prior to commencing in vitro experiments followed by clinical trials. This computerized experimental study aids in predicting the molecular mechanism of chimeric protein and how it interacts with both ligands. We have anticipated various features of the chimeric protein in terms of qualitative analysis (structure, protein modelling, physiological properties) and functional analysis (antigenicity, allergenicity, its receptor-ligand binding ability, involving signalling pathways). Furthermore, the reliability and validation of the binding mode of the chimeric protein against receptors were performed through a complex molecular dynamics simulation for a 100 ns timeframe in an aqueous environment. The obtained simulation study showed that CD30 was a better approachable marker as compared to CD20 due to its better binding energy score and also binding conformations stability.
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