Abstract
Introduction
Systemic lupus erythematosus (SLE) is a complex autoimmune disease driven by abnormal activation of B cells and plasma cells, resulting in persistent pathogenic autoantibody production. Managing refractory SLE (rSLE) is challenging due to disease heterogeneity and limited therapies. CD19 CAR-T therapy depletes B cells and induces remission, but spares long-lived plasma cells, allowing ongoing autoantibody production and relapse. Dual targeting of B cells and plasma cells may enable more comprehensive depletion of autoreactive cells and achieve deeper, longer-lasting remission. GC012F, a novel CD19/BCMA dual-targeting CAR-T-cell therapy product manufactured via a next-day FasTCAR-T process, is being investigated as a therapeutic option for rSLE. We report updated 12-month data from study NCT05846347, evaluating GC012F's safety and efficacy in rSLE, as well as effects on autoantibody levels and B and plasma cell populations to assess immune reset potential.
Methods
This open-label, single-arm study enrolled patients with rSLE (failed at least two immunosuppressants and one biologic). Participants received lymphodepletion followed by a single GC012F infusion (1, 2, or 3 × 10⁵ CAR+ T cells/kg) on day 0. Immunosuppressants were stopped at least one week before leukapheresis; bridging therapy was permitted. CRS and ICANS were graded per ASTCT 2019 criteria, with other adverse events per CTCAE v5.0. Efficacy endpoints included achievement of LLDAS and DORIS remission, changes in ANA and ENA profile, and discontinuation of SLE therapies.
Results
By April 20, 2025, 15 rSLE patients received a single GC012F infusion across three dose levels (DL1:n=3, DL2:n=3, DL3:n=9). Median follow-up was 531 days (range, 335–685). Median age was 28 years, 93% were female, and 11/15 (73.3%) patients had biopsy-proven lupus nephritis (class III =1, class IV =1, class III+V = 4, class IV+V = 2, class V=1). Median disease duration was 7.3 (range, 1.3–23.7) years and baseline SLEDAI was 12. Major organ involvements included arthritis, rash, and renal disease. Median baseline proteinuria was 1.58 g/day (range, 0.04-5.83 g/day).
No dose-limiting toxicities were observed in 15 patients. CRS occurred in 14 (mainly Grade 1); two Grade 3 events at the highest dose resolved after steroids. One patient had reversible Grade 2 ICANS. No serious or opportunistic infections occurred. GC012F showed strong in vivo expansion (median peak 40,270 copies/μg DNA, Tmax 10 days). B cells were fully depleted and reconstituted at a median of 56 days, predominantly with a naïve phenotype. All immunosuppressive therapies were discontinued post-infusion, except for low-dose corticosteroid in one patient with baseline renal impairment.
Improvements were observed in serological antibody levels, including significant reductions and sero-reversion in dsDNA, ANA and ENA profile and normalization of complement levels. SLEDAI scores declined persistently from baseline in all patients. By one-year post-infusion, 60% (9/15) achieved DORIS remission and 66.7% (10/15) achieved LLDAS. Four patients who did not achieve DORIS remission were primarily limited by residual proteinuria; however, after administration of GC012F, their proteinuria continued to decline. Patients attaining DORIS/LLDAS remission were able to sustain their remission status at subsequent follow-up assessments.
Conclusion
GC012F, a BCMA/CD19 dual-targeting CAR T- cell therapy, showed a tolerable safety profile with most patients achieving and maintaining DORIS remission and LLDAS. Patients not in remission still had improved disease activity. An ongoing phase 1/2 trial (NCT06530849) is further evaluating its safety and efficacy in a larger cohort.
