近日，北京大学魏文胜及其小组的最新研究探明了聚糖屏蔽使TCR能够进行足够的同种异体CAR-T治疗。这一研究成果发表在2025年8月21日出版的国际学术期刊《细胞》上。
该研究组发现信号肽肽酶样3 （SPPL3）缺失使原代T细胞中聚糖介导的免疫逃避成为可能。SPPL3缺失修饰了T细胞上的聚糖谱，限制了配体的可及性，降低了异体免疫，但不影响抗CD19 CAR分子的功能。在一项I期临床试验中，SPPL3无效，T细胞受体（TCR）缺陷的抗CD19异体CAR-T细胞达到了安全性的主要终点，9例复发/难治性B细胞非霍奇金淋巴瘤（B-NHL）患者中有3例观察到3级或更高级别的细胞因子释放综合征（CRS）（临床试验：NCT06014073）。逆向翻译研究强调了TCR在维持T细胞持久性中的关键作用。因此，该课题组研究人员评估了SPPL3无效、TCR充足的CAR-T治疗对3例淋巴瘤或白血病患者的安全性，并没有观察到移植物抗宿主病的临床症状。他们的研究结果表明，通过SPPL3缺失来屏蔽聚糖是优化通用CAR-T疗法的一个有希望的方向。
据了解，尽管自体嵌合抗原受体(CAR)-T细胞疗法取得了成功，但在同种异体环境中实现持久性和避免排斥反应仍然具有挑战性。
附：英文原文
Title: Glycan shielding enables TCR-sufficient allogeneic CAR-T therapy
Author: Zeguang Wu, Jinhong Shi, Qiezhong Lamao, Yuanyuan Qiu, Jinxin Yang, Yang Liu, Feifei Liang, Xue Sun, Wei Tang, Changya Chen, Qingming Yang, Chunmeng Wang, Zhifang Li, Haixia Zhang, Zhonghan Yang, Yunyi Zhang, Yuting Yi, Xufen Zheng, Yu Sun, Kuiying Ma, Lingling Yu, Huihui Yang, Zhaoxuan Wang, Wenjuan Zheng, Ling Yang, Zhixuan Zhang, Yongjian Zhang, Zhiqiang Wu, Yao Wang, Catherine C.L. Wong, Ming Jin, Pengfei Yuan, Weidong Han, Wensheng Wei
Issue&Volume: 2025-08-21
Abstract: Despite the success of autologous chimeric antigen receptor (CAR)-T cell therapy, achieving persistence and avoiding rejection in allogeneic settings remains challenging. We showed that signal peptide peptidase-like 3 (SPPL3) deletion enabled glycan-mediated immune evasion in primary T cells. SPPL3 deletion modified glycan profiles on T cells, restricted ligand accessibility, and reduced allogeneic immunity without compromising the functionality of anti-CD19 CAR molecules. In a phase I clinical trial, SPPL3-null, T cell receptor (TCR)-deficient anti-CD19 allogeneic CAR-T cells reached the safety primary endpoint, with grade 3 or higher cytokine release syndrome (CRS) observed in 3 out of 9 patients with relapsed/refractory B cell non-Hodgkin lymphoma (B-NHL) (ClinicalTrials.gov: NCT06014073). Reverse translational research highlighted the pivotal role of TCR in sustaining T cell persistence. We therefore evaluated the safety of SPPL3-null, TCR-sufficient CAR-T therapy on three patients with lymphoma or leukemia for compassionate care and observed no clinical signs of graft-versus-host disease. Our findings suggest glycan shielding by SPPL3 deletion is a promising direction for optimizing universal CAR-T therapies.
DOI: 10.1016/j.cell.2025.07.046
Source: https://www.cell.com/cell/abstract/S0092-8674(25)00910-9