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传统的治疗方法(如手术、放疗和化疗)在复发性和难治性肿瘤的治疗中往往存在着局限性,因此,免疫治疗、细胞治疗等新型肿瘤治疗策略正逐渐在临床肿瘤治疗中发挥巨大作用。其中,嵌合抗原受体T细胞(chimeric antigen receptor T cell,CAR-T)疗法是近年来发展迅速的肿瘤过继性细胞疗法,尤其是在血液系统肿瘤的治疗中卓有成效。截至目前,美国食品药品监督管理局先后批准了6种分别基于CD19及B细胞成熟抗原(BCMA)的CAR-T疗法,极大地推动了血液系统肿瘤治疗策略的快速发展[1] 。
CAR-T通过与靶细胞形成免疫突触来表达促凋亡配体,并释放细胞毒性穿孔素和颗粒酶以及分泌促炎细胞因子(如干扰素α、干扰素γ和白细胞介素2)来杀伤靶细胞。以CD19为靶点的T细胞疗法是目前CAR-T疗法中最具代表性的形式,其通过基因工程改造自体T细胞来表达特异性CD19抗原受体,从而以高亲和力攻击CD19阳性的恶性肿瘤细胞,并产生持久的反应[2],尤其是在白血病和淋巴瘤的治疗中疗效显著[3]。但CAR-T疗法治疗实体瘤的效果不尽人意,究其原因可能与肿瘤特异性靶点的难以确定、实体瘤复杂的免疫抑制微环境以及CAR-T向肿瘤部分的转运有限等相关[4]。同时CAR-T疗法通常可能会伴随着严重的不良反应,如靶点外毒性、脑毒性、神经毒性及严重的细胞因子风暴[5]。Ma等[6]研究发现,可通过借助辅助诊断克服T细胞特性和肿瘤环境所造成的障碍,即对CAR-T体内动态进行监测,可更大程度地提高CAR-T疗法在实体瘤中的疗效和安全性。
传统的影像学方法(如CT、MRI)可通过对肿瘤大小和形态变化的检测来提供肿瘤相关形态学信息,但无法检测T细胞的空间信息[7]。外周血液检测虽可检测循环中过继转移的T细胞、免疫标志物及相关细胞因子,但也不能提供T细胞的空间分布状态和肿瘤特异性的扩张情况,因而难以准确量化T细胞的肿瘤浸润程度[8]。肿瘤组织活检采样通常只包含一小部分肿瘤组织,因而也不能完全反映T细胞在整个肿瘤中的浸润情况[7]。基于放射性核素的CAR-T显像,可无创、实时、定量评价T细胞在体内的分布,是提供T细胞的空间信息、实现CAR-T疗法动态监测的关键,对CAR-T疗法的疗效预测及安全性评价具有重要的指导意义。
目前,基于放射性核素T细胞显像的方法主要包括3大类:直接标记显像、报告基因显像和内源性细胞显像,笔者将对这3种显像方法的优劣势进行综述,并展望未来的发展方向。
放射性核素探针在嵌合抗原受体T细胞治疗显像中的应用
Application of radionuclide probes in chimeric antigen receptor T cell therapy imaging
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摘要: 嵌合抗原受体T细胞(CAR-T)疗法是一种新型的过继细胞疗法,近几年在肿瘤治疗领域中受到广泛关注,尤其是在血液系统肿瘤(如急性淋巴细胞白血病和弥漫性大B细胞淋巴瘤)的治疗中发挥着关键作用。但该疗法受复杂的肿瘤微环境、靶点特异性等因素影响而在实体瘤中的应用较为有限。基于放射性核素的分子成像,通过对T细胞体内状态进行示踪,可更好地实现CAR-T的可视化与治疗监测,并反映CAR-T的功能信息与免疫状态,对CAR-T疗法疗效的预测与安全性评价具有重要的指导意义。笔者将系统介绍基于放射性核素的分子成像策略在CAR-T疗法应用中的最新进展。Abstract: Chimeric antigen receptor T cell (CAR-T) therapy is a novel adoptive cell therapy, and has received extensive attention in the field of tumor therapy in recent years, especially in the treatment of hematological tumors, such as acute lymphoblastic leukemia and diffuse large B-cell lymphoma. However, its application in solid tumors is limited because of the complex tumor microenvironment and target specificity. Molecular imaging based on radionuclides can better realize the visualization and therapeutic monitoring of CAR-T cells, and reflect the functional information and immune status of CAR-T cells, which has important guiding significance for the prediction and safety evaluation of CAR-T cells. This review will systematically introduce the latest advances in the application of radionuclide based molecular imaging strategies in CAR-T therapy.
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Key words:
- Molecular probes /
- Radionuclide imaging /
- Immunotherapy /
- Chimeric antigen /
- Isotope labeling /
- Genes, reporter
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