Article
作者: Liu, Yang ; Liang, Feifei ; Zheng, Wenjuan ; Yang, Huihui ; Han, Weidong ; Yang, Ling ; Jin, Ming ; Sun, Yu ; Yuan, Pengfei ; Wu, Zhiqiang ; Zhang, Yongjian ; Li, Zhifang ; Zhang, Yunyi ; Yang, Qingming ; Yi, Yuting ; Wang, Yao ; Zhang, Zhixuan ; Wang, Chunmeng ; Yu, Lingling ; Yang, Zhonghan ; Shi, Jinhong ; Yang, Jinxin ; Wong, Catherine C L ; Zheng, Xufen ; Qiu, Yuanyuan ; Zhang, Haixia ; Ma, Kuiying ; Wu, Zeguang ; Lamao, Qiezhong ; Tang, Wei ; Wei, Wensheng ; Sun, Xue ; Chen, Changya ; Wang, Zhaoxuan
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.