Background/Purpose: Refractory autoimmune diseases with progressive organ damage remain a major unmet medical need. C-CAR168 is an autologous anti-CD20/BCMA bispecific CAR-T therapy designed to simultaneously target autoantibody-producing plasma cells and their B-cell precursors, aiming to achieve a complete “immune reset”. This first-in-human Phase I trial (NCT06249438) evaluates C-CAR168 in patients with treatment-refractory autoimmune diseases. Here, we report the trial’s safety data and preliminary efficacy in the lupus nephritis (LN) and multiple sclerosis (MS) cohorts.

Methods: This Phase I, open-label study enrolled patients with refractory SLE (±LN), immune mediated necrotizing myositis (IMNM), neuromyelitis optica spectrum disorder (NMOSD), and MS, who had failed ≥2 standard immunosuppressive therapies. After lymphodepletion, patients received a single C-CAR168 infusion at either 0.75×10⁶ or 1.5×10⁶ CAR-T cells/kg.

Results: As of September 10, 2025, 16 patients were treated: 11 SLE (9 proliferative LN), 2 NMOSD, 2 progressive MS and 1 IMNM, with a median follow-up of 177 days. C-CAR168 was well tolerated. Grade 1-2 CRS occurred in 11/16 patients (68.8%) and resolved with supportive care. No ICANS or DLTs were observed. Grade ≥3 AEs were primarily hematologic and transient. Prolonged cytopenia and Grade 3 treatment-emergent infections each occurred in 2 patients (12.5%) and were successfully managed with standard therapies. All patients discontinued immunosuppressants (IS) / biologic agents, 12 (75%) achieved steroid discontinuation and 4 remained on corticosteroids ≤10 mg/day.

Robust efficacy was observed in the LN and SPMS patients. In proliferative LN (median 4 prior IS/ biologic agents, excluding steroids/HCQ), 7/9 patients achieved a renal response (77.8%), including 3 CR, 1 PERR and 3PR. Improvement in proteinuria was rapid (median 1M [range 1–3]), and continued to improve with longer follow-up. Improvement in extrarenal SLE activity, as measured by SRI-4, was achieved in 6/7 (85.7%) proliferative LN patients with ≥3M follow-up. The first SPMS patient showed significant improvement in gait and orbital movement, EDSS score, reductions in MRI lesion burden, and normalization of serum neurofilament light chain.

C-CAR168 expansion was accompanied by rapid depletion of CD20⁺ B cells and plasma cells in blood, followed by naïve-dominant B-cell reconstitution in most patients by months 2-3, along with reductions in the type I IFN gene signature score. In one patient, bone marrow biopsy confirmed complete plasma cell depletion. Longitudinal examination of the B cell receptor repertoire (BCR) in 3 LN patients revealed a loss of clonally expanded BCRs with subsequent emergence of a naïve repertoire after treatment.

Conclusion: C-CAR168 therapy demonstrated durable treatment-free disease control in refractory autoimmune diseases. Its favorable safety profile, together with a renal response rate of 77.8% in refractory proliferative LN and rapid neurological improvement in SPMS, both achieved without background standard of care medications, coupled with mechanistic evidence of immune reset, provides a compelling rationale for further clinical evaluation of C-CAR168.

ACR Meeting Abstracts - https://acrabstracts.org/abstract/anti-cd20-bcma-bispecific-car-t-cell-therapy-promotes-immune-reset-and-sustained-drug-free-remission-in-refractory-autoimmune-diseases/