CRISPR-Engineered Allogeneic CAR-T Cells Induce Remission in Refractory Lupus
Five patients with severe refractory SLE received YTS109, an allogeneic anti-CD19 T-cell product engineered with CRISPR-Cas9 to knock out five genes including TRAC, PD1, and HLA loci. All patients achieved clinical remission by month 3 with sustained responses and renal restoration confirmed by biopsy. This phase 1 study demonstrates that CRISPR-edited off-the-shelf cell products can be monitored via B-cell depletion kinetics and standard autoimmune serological panels.
The original study
Allogeneic CD19-targeting T cells for treatment-refractory systemic lupus erythematosus: a phase 1 trial.
- Authors
- Wang X, Zhang Y, Wang H, Wu X, He C, Lin S, et al.
- Journal
- Nature medicine
- Type
- Journal Article, Clinical Trial, Phase I
- PMID
- 40866583
Original 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 .