Wu Zeguang, Shi Jinhong, Lamao Qiezhong, Qiu Yuanyuan, Yang Jinxin, Liu Yang, Liang Feifei, Sun Xue, Tang Wei, Chen Changya, Yang Qingming, Wang Chunmeng, Li Zhifang, Zhang Haixia, Yang Zhonghan, Zhang Yunyi, Yi Yuting, Zheng Xufen, Sun Yu, Ma Kuiying, Yu Lingling, Yang Huihui, Wang Zhaoxuan, Zheng Wenjuan, Yang Ling, Zhang Zhixuan, Zhang Yongjian, Wu Zhiqiang, Wang Yao, Wong Catherine C L, Jin Ming, Yuan Pengfei, Han Weidong, Wei Wensheng
Biomedical Pioneering Innovation Center, Peking-Tsinghua Center for Life Sciences, Peking University Genome Editing Research Center, State Key Laboratory of Gene Function and Modulation Research, School of Life Sciences, Peking University, Beijing 100871, China; Changping Laboratory, Beijing 102206, China.
School of Medicine, Nankai University, Tianjin 300071, China; Department of Bio-Therapeutic, the First Medical Center, Chinese PLA General Hospital, Beijing 100039, China.
Cell. 2025 Aug 14. doi: 10.1016/j.cell.2025.07.046.
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.
尽管自体嵌合抗原受体（CAR）-T细胞疗法取得了成功，但在异基因环境中实现持久性并避免排斥反应仍然具有挑战性。我们发现，信号肽酶样3（SPPL3）缺失可使原代T细胞通过聚糖介导实现免疫逃逸。SPPL3缺失改变了T细胞上的聚糖谱，限制了配体的可及性，并降低了异基因免疫反应，同时不影响抗CD19 CAR分子的功能。在一项I期临床试验中，缺失SPPL3、缺乏T细胞受体（TCR）的抗CD19异基因CAR-T细胞达到了安全性主要终点，9例复发/难治性B细胞非霍奇金淋巴瘤（B-NHL）患者中有3例出现3级或更高等级的细胞因子释放综合征（CRS）（ClinicalTrials.gov：NCT06014073）。反向转化研究突出了TCR在维持T细胞持久性中的关键作用。因此，我们评估了缺失SPPL3、TCR充足的CAR-T疗法对三名淋巴瘤或白血病患者进行同情治疗的安全性，未观察到移植物抗宿主病的临床迹象。我们的研究结果表明，通过缺失SPPL3进行聚糖屏蔽是优化通用CAR-T疗法的一个有前景的方向。
