CLINICAL IMPACT OF C-CAR168, A NOVEL ANTI-CD20/BCMA COMPOSITE AUTOLOGOUS CAR T THERAPY, IN REFRACTORY LUPUS NEPHRITIS

O027 / #730 Topic: AS24 - SLE-Treatment Late-Breaking Abstract ABSTRACT CONCURRENT SESSION 04: ADVANCING LUPUS THERAPIES AND INSIGHTS 22-05-2025 1:40 PM - 2:40 PM Background/Purpose Despite advances in targeted therapies, refractory lupus nephritis (LN) represents a significant therapeutic challenge. C-CAR168 is a novel composite CAR T cell therapy directed against CD20 and B-cell maturation antigen (BCMA), that simultaneously targets mature B cells and plasma cells, both involved in lupus pathogenesis.[1] We report initial findings from 7 patients with severe LN in this first-in-human study ( NCT06249438 ). Methods This is a phase 1, open-label, dose-escalation and expansion study to evaluate the safety, efficacy and cellular kinetics of C-CAR168. For entry, patients must have biopsy-proven LN, increased 24h urinary protein (UP ≥ 1.0 g/24h) or urinary protein-to-creatinine ratio (UPCR) ≥ 1000 mg/g and have been exposed to ≥ 2 immunosuppressants (IS) and/or biologic agents. Eligible patients underwent steroid and IS tapering, leukapheresis, and lymphodepletion followed by a single infusion of C-CAR168. Clinical and laboratory features were monitored and CAR T cell kinetics were assessed by quantitative PCR and flow cytometry. Results As of January 14th, 2025, 7 patients with refractory LN received C-CAR168 therapy, with 4 dosed at 0.75×10^6 cells/kg and 3 at 1.5×10^6 cells/kg. The treated population had long-standing refractory disease (median SLE duration 9 years, LN 5 years) with exposure to a median of 4 IS or biologic agents. Renal histology showed predominantly mixed proliferative and membranous patterns. Active disease was evidenced by elevated proteinuria (UP range: 1227.2-8156.9 mg/24h) and SLEDAI-2K scores (range: 8-24) (Table 1) Table 1. With median follow-up of 121 days, treatment-emergent adverse events included cytokine release syndrome in 4 patients (57.1%), all grade 1-2, with median onset at day 1 and resolution within 8 days. One patient experienced transient grade 3-4 thrombocytopenia (days 9-13) that was resolved with platelet transfusion. Notably, no immune effector cell-associated neurotoxicity syndrome, severe infections, or serious adverse events were observed. Clinical response was marked by successful withdrawal of all IS, with 4 patients (57.1%) also discontinuing steroids, whereas 3 continued on low-dose prednisone (5-10 mg/d). The first 2 evaluable patients at 6 months achieved SLE Responder Index-4 and ≥ 50% reduction in proteinuria, with one also achieving Definition Of Remission In SLE (DORIS), Lupus Low Disease Activity State (LLDAS) and complete renal response. One patient with shorter follow-up showed early complete renal response at month 3. All patients maintained stable renal function without deterioration in estimated glomerular filtration rate. Most patients demonstrated improvements in disease activity measures (SLEDAI-2K, PhGA) and serological improvements including complement normalization and reduction in anti-dsDNA antibodies (Figure 1). C-CAR168 expanded in all patients along with a rapid and profound depletion of circulating CD20+ B cells and plasma cells. B cells recovered in 6/7 patients by month 2 with the majority of recovered B cells being naïve B cells. Substantial decreases of blood plasma cell and type 1 IFN gene signature scores[2,3] were observed post treatment (Figure 1). Figure 1. Conclusions Initial results show promising efficacy and safety of C-CAR168 treatment in refractory LN, with reduced proteinuria, preserved renal function and improvement in laboratory and extrarenal features of LN, enabling withdrawal of IS. While the safety profile and early response signals are favorable, larger trials with longer follow-up are needed to validate the clinical impact of C-CAR168 in treatment of refractory LN. References: [1.] Huang J. Arthritis Rheumatol 2024;76 (suppl 9). [2.] Streicher K. Arthritis Rheumatol 2014;66(1):173-84. [3.] Yao Y. Hum Genomics Proteomics 2009;2009:374312.

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