引言
嵌合抗原受体-T(CAR-T)细胞治疗是一种新的免疫治疗方法，具有显著的临床成功。然而，由于制备时间长、成本高、人与人之间的差异，它们的应用受到限制。尽管通用CAR-T (U-CAR-T)细胞的制造有了显著的进步，但它们仍然不是一个稳定和统一的细胞库。
2024年3月11日，中山大学张辉及广州实验室马显才共同通讯在
Molecular Cancer（IF 37）在线发表题为“
The construction of modular universal chimeric antigen receptor T (MU-CAR-T) cells by covalent linkage of allogeneic T cells and various antibody fragments”的研究论文，该研究构建了一种新型模块化通用CAR-T (MU-CAR-T)细胞来进一步提高U-CAR-T细胞的便利性和灵活性。
首先筛选健康供体并培养其T细胞，以获得更高比例的干细胞样记忆T (T
SCM)细胞，这些细胞具有强大的自我更新能力、可持续性和细胞毒性。为了降低同种异体反应性，利用CRISPR/Cas9系统，通过双敲除T细胞受体(TCR)和I类人白细胞抗原(HLA-I)基因，进一步T细胞。携带CAR片段的生长良好且遗传稳定的通用细胞随后被储存为稳定统一的细胞库。随后，SDcatcher/GVoptiTag系统产生一个异肽键，用于将纯化的针对不同抗原的抗体的scFvs共价连接到回收的CAR-T细胞上。该研究产生的CAR-T细胞可以通过特异性靶向各种细胞来执行不同的功能，例如根除人类免疫缺陷病毒1型(HIV-1)潜伏感染的细胞或消除T淋巴瘤细胞，其效率与传统的CAR-T细胞相似。综上所述，该研究使CAR-T细胞的生产更加模块化，并使CAR-T细胞的质量控制和制药制造更加可行。
CAR-T细胞疗法代表了一种前沿和革命性的免疫治疗方法。
临床疗效显著，特别是在治疗血液系统恶性肿瘤方面，被认为是最有前途的抗肿瘤疗法之一。该方法也被提出作为治疗病毒感染的治疗策略，包括HIV-1、乙型肝炎病毒(HBV)、丙型肝炎病毒(HCV)和SARS-CoV-2。然而，传统CAR-T细胞的生产是个体化定制的，不利于大规模生产，导致患者准备时间延长。
因此，许多晚期或快速进展的疾病患者往往处于治疗选择有限的阶段。
同时，CAR-T细胞治疗在患者体内的疗效和持久性受到
肿瘤抗原异质性
、免疫抑制肿瘤微环境、抗原逃逸和T细胞耗竭等各种挑战的阻碍。
因此，可以同时靶向多种抗原或有效靶向泛表位的通用CAR-T细胞疗法是有希望的替代方法。
模块化CAR-T细胞系统的发展正在加速，与传统完整的CAR-T细胞不同，模块化CAR-T细胞系统可以通过适配器分离T细胞信号域和抗原识别域来精确控制CAR-T细胞。
适配系统也是目前通用CAR-T细胞研究的重点，如BBIR CAR、anti-GCN4 CAR、anti-FITC CAR、Spy CAR系统、Uni CAR、SUPRA CAR、Convertible CAR、BsAb适配CAR等。
这些不同的适配器共轭方法，其中大多数不是共价连接，通过交换不同的
单链可变片段
(scFvs)允许T细胞重定向，而无需频繁更换CAR和耗时的再制造。
由于其灵活性，这些方法显著提高了其临床适用性。
基于Sd/Gv平台的模块化CAR设计示意图（Credit:
Molecular Cancer）
维持T细胞在体内的长期存活和增殖能力是实现CAR-T治疗持续疗效的关键。
T
SCM
细胞是一种罕见的
淋巴细胞亚群
，具有长期存活能力和强大的免疫重建潜力。在临床前动物模型中，过继移植的T
SCM样CAR-T细胞表现出强大的增殖和抗肿瘤能力。此外，对CD19导向的CAR-T治疗反应更好的患者，其CAR-T储存库中记忆CAR-T细胞的频率也增加。
因此，扩增T细胞中TSCM亚群的比例与CAR-T疗法的治疗效果相关。
该研究提供了一种基于Sd/Gv系统的新型模块化通用CAR-T细胞生成平台。
结合不同的scFvs可以识别多种抗原。同时或顺序靶向多个TAAs有助于防止抗原逃逸。此外，它可以通过控制靶向配体的剂量来控制T细胞的反应功能或减少副作用。
总之，开发MU-CAR-T细胞疗法的最终目标是使其成为一种“活的药物”，可以在临床环境中高效、经济地应用于治疗肿瘤、自身免疫性疾病和传染病，如艾滋病和COVID-19。
|探索君
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文章来源|“iNature”
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