美国斯坦福大学Robbie G. Majzner团队的最新研究表明，协同信号分子实现CAR T细胞的逻辑门控。该项研究于2023年3月8日在线发表在《自然》杂志上。

研究人员表示，尽管嵌合抗原受体（CAR）T细胞已经改变了B细胞恶性肿瘤的治疗格局，但由于大多数目标抗原与正常细胞共享，靶向、非肿瘤毒性的风险已经阻碍了它们在实体瘤方面的发展。研究人员试图将布尔逻辑门控应用于CAR T细胞，以防止毒性；然而，真正安全和有效的逻辑门控CAR仍然遥不可及。

研究人员描述了一种CAR工程的方法，其用细胞内的近端T细胞信号分子取代传统的CD3ζ结构域。结果表明，某些近端信号的CAR，如ZAP-70 CAR，可以激活T细胞并在体内消灭肿瘤，同时绕过上游信号蛋白，包括CD3ζ。ZAP-70的主要作用是磷酸化LAT和SLP-76，它们形成了一个信号传播的支架。研究人员利用LAT和SLP-76的合作作用，设计了逻辑门控细胞内网络（LINK）CAR，这是一个快速和可逆的布尔逻辑AND门控CAR T细胞平台，在疗效和防止靶向、非肿瘤毒性方面都优于其他系统。LINK CAR将扩大CAR T细胞可以靶向的分子范围，并使这些强大的治疗药物能够用于实体瘤和各种疾病，如自身免疫和纤维化。此外，这项工作表明，细胞的内部信号机制可以被重新利用为表面受体，这可能为细胞工程开辟新的途径。

附：英文原文

Title: Co-opting signalling molecules enables logic-gated control of CAR T cells

Author: Tousley, Aidan M., Rotiroti, Maria Caterina, Labanieh, Louai, Rysavy, Lea Wenting, Kim, Won-Ju, Lareau, Caleb, Sotillo, Elena, Weber, Evan W., Rietberg, Skyler P., Dalton, Guillermo Nicolas, Yin, Yajie, Klysz, Dorota, Xu, Peng, de la Serna, Eva L., Dunn, Alexander R., Satpathy, Ansuman T., Mackall, Crystal L., Majzner, Robbie G.

Issue&Volume: 2023-03-08

Abstract: Although chimeric antigen receptor (CAR) T cells have altered the treatment landscape for B cell malignancies, the risk of on-target, off-tumour toxicity has hampered their development for solid tumours because most target antigens are shared with normal cells1,2. Researchers have attempted to apply Boolean-logic gating to CAR T cells to prevent toxicity3,4,5; however, a truly safe and effective logic-gated CAR has remained elusive6. Here we describe an approach to CAR engineering in which we replace traditional CD3ζ domains with intracellular proximal T cell signalling molecules. We show that certain proximal signalling CARs, such as a ZAP-70 CAR, can activate T cells and eradicate tumours in vivo while bypassing upstream signalling proteins, including CD3ζ. The primary role of ZAP-70 is to phosphorylate LAT and SLP-76, which form a scaffold for signal propagation. We exploited the cooperative role of LAT and SLP-76 to engineer logic-gated intracellular network (LINK) CAR, a rapid and reversible Boolean-logic AND-gated CAR T cell platform that outperforms other systems in both efficacy and prevention of on-target, off-tumour toxicity. LINK CAR will expand the range of molecules that can be targeted with CAR T cells, and will enable these powerful therapeutic agents to be used for solid tumours and diverse diseases such as autoimmunity7 and fibrosis8. In addition, this work shows that the internal signalling machinery of cells can be repurposed into surface receptors, which could open new avenues for cellular engineering.

DOI: 10.1038/s41586-023-05778-2

Source: https://www.nature.com/articles/s41586-023-05778-2