Wang Xiaobing, Zhang Yi, Wang Huimin, Wu Xin, He Chao, Lin Suxian, Pang Kun, Li Yang, Chen Yue, Tang Xiaojing, Liu Xin, Wang Jiazheng, Ye Songying, Yan Ran, Guan Tongxiang, Dai Bing, Lu Jing, He Haiyan, Lin Li, Lu Hongjuan, Li Ting, Zhou Ling, Ye Lingying, Zhao Juan, Liu Yanfang, Ta Na, Wu Jun, Cai Wanshi, Wan Zhe, Zhang Shasha, Sun Ruya, Zhao Xueqiang, Wang Jiasheng, Lin Yong, Ning Beifang, Zhao Zhengqing, Tang Xiaofeng, Du Juan, Mao Zhiguo, He Yanran, Zheng Hongli, Sun Lingyun, Lin Xin, Xu Huji
Department of Rheumatology and Immunology, National key laboratory for immunity and inflammation, Changzheng Hospital, Naval Medical University, Shanghai, China.
Institute for Immunology and School of Basic Medical Sciences, Tsinghua University, Beijing, China.
Nat Med. 2025 Aug 27. doi: 10.1038/s41591-025-03899-x.
Commercial autologous anti-CD19 chimeric antigen receptor-T cell therapies are effective in B cell malignancies and autoimmune diseases but are limited by personalized manufacturing, high costs and the risk from random chimeric antigen receptor insertion into the genome. To overcome these challenges, we developed YTS109, a hypoimmune allogeneic T cell product engineered using CRISPR-Cas9 to knock out TRAC, PD1, HLA-A, HLA-B and CIITA, with a CD19-targeting synthetic TCR and antigen receptor (STAR) precisely integrated into the TRAC locus to enable physiological, TCR-like signaling. As part of a multi-disease cohort trial, this article includes all enrolled five patients with severe, refractory systemic lupus erythematosus (SLE) complicated by lupus nephritis, who received lymphodepletion followed by YTS109 at 3 × 10 STAR⁺ T cells per kg body weight. Primary endpoints were safety and SLE responder index 4 at month (M) 3. Secondary endpoints included clinical remission and quality-of-life outcomes through to M6. YTS109 was well tolerated, with only mild cytokine release syndrome and no graft-versus-host disease. All five patients in the SLE cohort achieved SLE responder index 4 response at M3, which was sustained through to M6. Four of five patients showed a rapid and sustained reduction in SLE disease activity score (mean 31.30-5.35 by M6), while one patient showed a mild refractory flare-up at M6. Quality-of-life improvements were observed across all four instruments in five patients by 6 months after infusion. Renal biopsies further confirmed resolution of inflammation and tissue restoration. These results demonstrate that YTS109 induced immune resetting and clinical remission, including renal structural restoration, potentially offering a promising therapy for refractory SLE with severe lupus nephritis, pending further validation. ClinicalTrials.gov registration: NCT06379646 .
商业化的自体抗CD19嵌合抗原受体T细胞疗法在B细胞恶性肿瘤和自身免疫性疾病中有效，但受个性化生产、高成本以及嵌合抗原受体随机插入基因组带来的风险限制。为克服这些挑战，我们开发了YTS109，这是一种低免疫原性的同种异体T细胞产品，利用CRISPR-Cas9技术敲除TRAC、PD1、HLA-A、HLA-B和CIITA，并将靶向CD19的合成T细胞受体和抗原受体（STAR）精确整合到TRAC位点，以实现生理性的、类似T细胞受体的信号传导。作为一项多病种队列试验的一部分，本文纳入了所有入组的5例患有严重难治性系统性红斑狼疮（SLE）并伴有狼疮性肾炎的患者，他们先接受淋巴细胞清除，然后按每千克体重3×10个STAR⁺T细胞的剂量接受YTS109治疗。主要终点是第3个月（M3）时的安全性和SLE反应指数4。次要终点包括直至M6的临床缓解和生活质量结果。YTS109耐受性良好，仅出现轻度细胞因子释放综合征，未发生移植物抗宿主病。SLE队列中的所有5例患者在M3时均达到SLE反应指数4反应，并持续至M6。5例患者中有4例SLE疾病活动评分迅速且持续降低（到M6时平均从31.30降至5.35），而1例患者在M6时出现轻度难治性病情复发。输注后6个月，5例患者在所有四项评估工具上的生活质量均得到改善。肾活检进一步证实炎症消退和组织修复。这些结果表明，YTS109诱导了免疫重置和临床缓解，包括肾脏结构恢复，这可能为难治性SLE伴严重狼疮性肾炎提供一种有前景的治疗方法，有待进一步验证。ClinicalTrials.gov注册号：NCT06379646 。
