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通过调节p53信号网络与Δ133p53α,增强仿真抗原受体T细胞疗法

Christopher Roselle^1,2, Izumi Horikawa³, Linhui Chen¹

¹Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.

Proceedings of the National Academy of Sciences of the United States of America

|February 26, 2024

概括

在嵌合式抗原受体 (CAR) T 细胞中构成性表达 Δ133p53α 增强了抗瘤活性并对抗功能障碍. 这一策略改善了慢性淋巴细胞白血病 (CLL) 患者的CAR T细胞疗效,提供了潜在的治疗进展.

科学领域:

免疫学免疫学免疫学
癌症生物学癌症生物学
分子生物学分子生物学

背景情况:

在CLL等血液癌症中,CAR T细胞功能障碍限制了持久的缓解.
内源性p53异型,Δ133p53α,随着年龄的增长而下降,可以恢复T细胞的增殖.
Δ133p53α调节p53应激反应,而没有交换活化域.

研究的目的:

研究构成型Δ133p53α表达对CAR T细胞功能和抗瘤活性的影响.
为了确定 Δ133p53α 表达能否在压力条件下克服CAR T细胞功能障碍.
评估D133p53α在CLL患者的CAR T细胞治疗中的治疗潜力.

主要方法:

工程 CD19 导向的 CAR T 细胞以构成性表达 Δ133p53α.
在营养限制和高瘤负担条件下评估CAR T细胞增殖,效应器功能和代谢表型.
在CLL患者衍生模型中评估了表达Δ133p53α的CAR T细胞的疗效.

主要成果:

Δ133p53α表达增强了抗瘤活性和有限的CAR T细胞功能障碍.
表达Δ133p53α的CAR T细胞表现出增强的代谢适应性,保持效应器功能和增殖.
改进的线粒体功能和高调的生物合成过程有助于提高CAR T细胞的性能.
来自CLL患者的CAR T细胞用Δ133p53α进行工程改造,即使在先前治疗失败后,也显示出更好的抗瘤疗效.

结论:

构成性Δ133p53α表达增强了CAR T细胞的抗瘤有效性和对功能障碍的弹性.
通过Δ133p53α调节p53应激反应,可以改善CAR T细胞的新陈代谢和功能.
这一策略有望改善CLL和其他血液性恶性瘤中CAR T细胞治疗结果.

关键词:

一个T细胞细胞.癌症治疗疗法癌症治疗衰老是一种老化.

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