Abstract
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 × 106 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.
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Data availability
The raw single-cell sequencing data and 10x Visium HD sequencing data reported in this study are available from the Genome Sequence Archive for Human under accession no. HRA011753. The processed single-cell transcriptomic, spatial transcriptomic, mass cytometry and proteomic data reported in this study have been deposited at Zenodo (https://doi.org/10.5281/zenodo.15715577). Individual-level clinical data are available under restricted access because of patient privacy and ethical considerations. Qualified researchers may request access by contacting the corresponding author. Requests will be reviewed by the study’s data access committee to ensure compliance with institutional and regulatory policies. Responses to data access requests can be expected within 2–4 weeks.
Code availability
The code for sequencing processing and data analysis is available at Zenodo (https://doi.org/10.5281/zenodo.15597470).
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Acknowledgements
This study was partially supported by BriSTAR Immunotech. H.X. is supported by the Natural Science Foundation of China (grant no. 82320108010) and the Shanghai Collaborative Innovation Cluster Program (grant no. 2024CXJQ01). X. Lin was supported by the National Natural Science Foundation of China (grant nos. 82293664, 82341212 and 31930039) and the Annual Fund from the Tsinghua-Peking Center for Life Sciences. X. Wang is supported by the Project of the National Key R&D Program of China (grant nos. 2024YFC2510306 and 2024YFC2510300), the Natural Science Foundation of China (grant no. 82271816) and the Clinical Research Project of the Shanghai Municipal Health Commission (grant no. 202440161). X. Wu is supported by the Natural Science Foundation of China (grant no. 82271852), the National Key R&D Program of China (grant no. 2022YFF1203100) and the Innovative Clinical Research Project of Shanghai Changzheng Hospital (grant no. 2020YCXYJ-QN04).
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Contributions
H.X. and X. Lin designed and supervised the study, and reviewed and edited the paper. X. Wang conducted the study and wrote the original draft. Y.Z. acquired the data and performed the clinical evaluation. L.S. and H.Z. supervised the study and edited the paper. Y.H. provided consultation and contributed to the review and editing of the paper. S.Z. and X.Z. monitored the clinical trial. H.W. and R.S. designed the STAR-T cell construct and Jiasheng Wang participated in the in vitro experiments. Y. Li and Z.W. were responsible for manufacturing and the quality control of the cell product. C.H., S.L., X. Liu and X. Wu managed the clinical care of patients. J.L., H.H., L.L., H.L., T.L., L.Z., L.Y., J.Z., Y. Lin, B.N., Z.Z., Xiaofeng Tang, J.D. and Z.M. assisted with the clinical evaluations. K.P., Jiazheng Wang and W.C. performed the bioinformatics analysis. Y.C., S.Y. and R.Y. collected and visualized the data. T.G. managed the nursing care. Xiaojing Tang and B.D. performed the renal biopsies. Y. Liu, N.T. and J. Wu conducted the renal pathology studies. All authors approved the final paper and vouched for the accuracy and completeness of the data.
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Extended data
Extended Data Fig. 1 Potential off-target cleavage sites identified by GUIDE-Seq and assessment of potential GVHD risk for YTS109 in NCG mice model.
a, The cleavage sites sequences and dsODN incorporation sites of TRAC, HLA-A/HLA-B, CIITA and PDCD-1 were detected by GUIDE-Seq, annotated as either on-target or off-target, the total number of unique alignments associated with the site, and the identifier Gene ID. b, NCG mice received 1 × 107 Mock-T or YTS109 cells (N = 7 animals per group). T cell expansion was monitored via blood collection from the tail vein at indicated timepoints. Body weight and survival rate were recorded. Data are presented as mean values +/− SEM. Statistical significance was determined with one-way ANOVA (left), two-tailed, unpaired two-sample t test (middle) or Log-rank (Mantel-Cox) test (right). ***p < 0.001; **p < 0.01; *p < 0.05.
Extended Data Fig. 2 Spatial transcriptomic profiling of renal biopsy revealed reduced immune activation and inflammation in the kidney after YTS109 treatment.
a, Multicolor immunofluorescence staining highlighting the distribution and alterations of CD4 (orange) cells. b, Spatial cell type distribution and clustering. HE staining (top); cell type annotation (middle); louvain clustering (bottom). Spatial transcriptomic analysis of renal tissue from Patient 1 before (top) and after (bottom) YTS109 treatment. c, Cell type composition of Cluster 1 (Glomerulus) at BL and M9, showing proportions of 29 annotated cell populations including podocytes, glomerular endothelial cells, monocytes, dendritic cells, T cells, epithelial cells, fibroblasts, and others.
Extended Data Fig. 3 Longitudinal single-cell profiling of peripheral immune compartments reveals individual dynamic immune reconstitution after YTS109 treatment.
a, Stacked bar plots showing the distribution and absolute number of peripheral immune cell populations over time across five patients. b, Stacked bar plots showing the distribution and absolute number of peripheral B cell subsets over time across five patients. c, Proportions and absolute numbers of peripheral B cell subsets after YTS109 treatment by Flow cytometry analysis (memory B cells, naïve B cells, and PBs in five patients before and after YTS109 infusion.
Extended Data Fig. 4 Analysis of plasma proteomics following YTS109 infusion.
a, Principal Component Analysis (PCA) plot for plasma. Dots demonstrate individual sample distribution before (Pre, orange) and after treatment (Post, blue). b, Volcano plot comparing the plasma protein expression at M3 and BL. Red indicates up-regulation at M3. c, Heatmap of differentially expressed proteins from plasma samples at BL, M1, M2, and M3. The color scale ranges from low (0.0) to high (1.0). d, GSEA items of the plasma protein at M3 and BL. Red bars represent up-regulated signaling pathways at M3, and blue bars represent down-regulated signaling pathways. P values were calculated by the two-sided Wilcoxon rank-sum test.
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Wang, X., Zhang, Y., Wang, H. et al. Allogeneic CD19-targeting T cells for treatment-refractory systemic lupus erythematosus: a phase 1 trial. Nat Med (2025). https://doi.org/10.1038/s41591-025-03899-x
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DOI: https://doi.org/10.1038/s41591-025-03899-x
