A groundbreaking phase 1 trial has demonstrated that an allogeneic CD19-targeting T cell therapy can safely and effectively treat patients with severe, treatment-refractory systemic lupus erythematosus (SLE) complicated by lupus nephritis. The study, published in Nature Medicine, represents the first clinical application of YTS109, a novel CRISPR-engineered cell therapy that addresses key limitations of current autologous CAR-T treatments.
Novel Engineering Approach Overcomes CAR-T Limitations
YTS109 represents a significant advancement in cell therapy design, utilizing CRISPR-Cas9 technology to create a hypoimmune allogeneic T cell product. The therapy involves knocking out five key genes (TRAC, PD1, HLA-A, HLA-B and CIITA) while precisely integrating a CD19-targeting synthetic TCR and antigen receptor (STAR) into the TRAC locus to enable physiological, TCR-like signaling.
This engineering approach directly addresses the major limitations of commercial autologous anti-CD19 chimeric antigen receptor-T cell therapies, which are effective in B cell malignancies and autoimmune diseases but are constrained by personalized manufacturing requirements, high costs, and risks from random chimeric antigen receptor insertion into the genome.
Strong Clinical Outcomes in Refractory Disease
The trial enrolled five patients with severe, refractory SLE complicated by lupus nephritis, who received lymphodepletion followed by YTS109 at 3 × 10⁶ STAR⁺ T cells per kg body weight. The primary endpoints were safety and SLE responder index 4 at month 3, with secondary endpoints including clinical remission and quality-of-life outcomes through month 6.
All five patients achieved the primary endpoint of SLE responder index 4 response at month 3, which was sustained through month 6. Four of five patients demonstrated rapid and sustained reduction in SLE disease activity score, with the mean score decreasing from 31.30 to 5.35 by month 6. One patient experienced a mild refractory flare-up at month 6.
Safety Profile and Mechanistic Evidence
YTS109 demonstrated a favorable safety profile, with patients experiencing only mild cytokine release syndrome and no graft-versus-host disease. B cell depletion was achieved in all patients, and renal B cell depletion was confirmed in two patients who underwent repeat kidney biopsies, coinciding with marked clinical remission in these individuals.
Quality-of-life improvements were observed across all four measurement instruments in five patients by 6 months after infusion. Importantly, renal biopsies further confirmed resolution of inflammation and tissue restoration, providing mechanistic evidence for the therapy's effectiveness.
Clinical Implications and Future Directions
The 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. However, the study has several acknowledged limitations, including its single-arm design, small sample size (n = 5) and short follow-up period.
As noted by Nicola Ferrari, Director of Translational Science Lead for Respiratory and Immunology at AstraZeneca, larger, longer-term studies are needed to confirm the durability and generalizability of responses. The trial is registered under ClinicalTrials.gov registration NCT06379646, indicating ongoing clinical development efforts.
