Systemic lupus erythematosus (SLE) and lupus nephritis (LN) are primarily driven by pathogenic autoantibodies produced by CD19-positive B cells and BCMA-positive plasma cells, including long-lived plasma cells (LLPCs). While CD19-targeted CAR-T therapy has shown encouraging results in immune system reprogramming, disease relapse remains a significant challenge due to antigen-negative or difficult-to-eradicate LLPCs. To overcome this limitation, ICG318 was developed as a dual-target CAR-T therapy that simultaneously targets CD19 on B cells and BCMA on plasma cells, aiming to eliminate both newly generated autoreactive B cells and persistent antibody-producing LLPCs for a deeper and more durable immune reset.
This investigator-initiated, multicenter, open-label Phase 1 study evaluated the long-term efficacy and safety of ICG318 in patients with refractory SLE and LN characterized by autoantibody production from B cells and plasma cells. Following lymphodepletion, patients received ICG318 at a dose of 3 × 10⁶ cells/kg. Patients with concurrent diffuse large B-cell lymphoma (DLBCL) received additional fludarabine. Twelve adult patients with refractory SLE were consecutively enrolled, including ten with biopsy-confirmed lupus nephritis and two with SLE complicated by DLBCL. The median follow-up duration was 30 months, ranging from 19 to 67 months.
The long-term efficacy results were notable. Ten out of twelve patients (83.3%) achieved strict complete remission, defined as drug-free DORIS remission, complete serological normalization, and complete renal response. Eleven patients achieved drug-free serological remission, while one patient reached a low disease activity state with minimal steroid and immunosuppressive therapy. In some patients, strict complete remission has been sustained for nearly six years. Disease activity improved substantially, with the mean SLEDAI-2K score decreasing from 9.5 at baseline to 0.5 at the last follow-up.
Pathogenic autoantibodies, including anti-dsDNA, anti-Sm, anti-nucleosome, and anti-SSA/Ro variants, were rapidly and durably eliminated. Complement levels (C3 and C4), which were reduced at baseline, normalized within one month and remained stable throughout follow-up, aside from isolated cases of low complement levels. Among the ten lupus nephritis patients, nine achieved complete renal response, with stable estimated glomerular filtration rate (eGFR) and significant improvement in proteinuria. Repeat kidney biopsies at one year demonstrated marked histological improvement, including disappearance of cellular crescents, reduced mesangial and endothelial proliferation, and attenuation of basement membrane spike formations.
ICG318 demonstrated a favorable long-term safety profile. No Grade 3 or higher cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS) was observed. Despite dual targeting of B cells and plasma cells, humoral immunity was successfully reconstituted, with immunoglobulin levels returning to normal within four to six months. Revaccination confirmed preserved immune responsiveness. Importantly, one patient experienced two successful natural pregnancies and delivered healthy full-term infants at 15 and 36 months after infusion, representing the first reported successful fertility outcome following dual-target CAR-T therapy in SLE.
Overall, this study demonstrates that dual-target CAR-T therapy with ICG318 can induce durable, drug-free remission and histological renal improvement in patients with refractory SLE and lupus nephritis. The sustained strict complete remission observed for nearly six years suggests that CAR-T therapy may offer the potential for long-term disease control in humoral autoimmune disorders. These findings support further evaluation of ICG318 in larger, randomized clinical trials.
