肿瘤细胞治疗研究
英文原题：Intein-based modular chimeric antigen receptor platform for specific CD19/CD20 co-targeting.
我们的研究为通过一种通用且惰性的CAR骨架，实现高度特异性激活以靶向多种抗原的新方法奠定了基础。
CAR-T 细胞疗法的发展已经彻底改变了B细胞恶性肿瘤的治疗，尽管抗原逃逸和肿瘤异质性等挑战往往会降低治疗成功率。靶向多种抗原的模块化CAR已被提出作为一种有趣的解决方案，通过降低肿瘤细胞因单一抗原丢失而逃避治疗的可能性来应对这些挑战。在本研究中，我们提出了一种新的模块化CAR平台，称为CARtein，它利用内含肽相互作用来共同靶向CD19和CD20抗原。我们证明，CARtein系统——其特点是一个通用CAR信号骨架，可与特定的scFv-内含肽识别伴侣共价结合——能够生成完全有活性的CAR。使用表达CD19和/或CD20的Raji细胞和K562细胞验证了其功能性，观察到通过NFAT和NFκB启动子活性以及CD69上调所体现的显著T细胞激活。总体而言，我们的研究为通过一个通用且惰性的CAR骨架建立一种具有高度特异性激活的靶向多种抗原的新方法奠定了基础。
Development of chimeric antigen receptor T-cell therapy has revolutionized the treatment of B-cell malignancies, although challenges such as antigen escape and tumor heterogeneity often decrease treatment success. Modular CARs targeting multiple antigens have been proposed as an interesting solution to address these challenges by reducing the likelihood of tumor cells evading treatment through the loss of a single antigen. In this study, we present a new modular CAR platform, termed CARtein, which takes advantage of intein interactions to jointly target CD19 and CD20 antigens. We demonstrate that the CARtein system, which features a universal CAR signaling backbone that covalently binds to specific scFv-intein recognition partners, generates fully active CARs. Functionality was validated using Raji cells and K562 cells expressing CD19 and/or CD20, observing significant T cell activation through NFAT and NFκB promoter activity and CD69 upregulation. Overall, our study lays the foundation for the establishment of a new way to target multiple antigens through a universal and inert CAR backbone with highly specific activation.
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