OC.56 Safety and early efficacy of rapcabtagene autoleucel, an autologous CD19-directed chimeric antigen receptor T-cell therapy, in severe refractory diffuse cutaneous systemic sclerosis

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Introduction Diffuse cutaneous systemic sclerosis (dcSSc) can be severe, with potential significant organ involvement, leading to end-organ failure and death. Therapeutic options for dcSSc are limited and inadequately address clinical manifestations or modify disease progression. CD19-targeted chimeric antigen receptor (CAR)-T cell therapy shows promise, with the potential to induce deep and sustained B cell depletion, thereby facilitating an immune system reset and offering the prospect of long-term remission in autoimmune diseases, including dcSSc. Material and Methods This Phase 2 open-label, AUTOGRAPH study (CYTB323K12201) evaluates rapcabtagene autoleucel, an autologous CD19-directed CAR-T cell therapy, in participants with severe, refractory (inadequate response to >2 prior systemic therapies) dcSSc. The study consists of two sequential cohorts: Cohort 1, a single-arm safety cohort, followed by a randomized and controlled Cohort 2. All participants in Cohort 1 underwent lymphodepleting chemotherapy with cyclophosphamide and fludarabine, followed by a single intravenous infusion of rapcabtagene autoleucel, with the initial three dosed sequentially with a 28-day observation period between participants; subsequent participants were dosed in parallel. All participants were hospitalized >=14 days post-infusion. Results Cohort 1 included 5 females and 1 male, with median: age of 49 years (range: 32–56), disease duration of 22 months (range: 10–35) and modified Rodnan skin score (mRSS) of 36.5 (range: 34–48); 5/6 participants were anti-Scl-70 positive and, 1/6 were anti-RNA polymerase 3 positive. All participants had progressive skin disease; two with concurrent progressive interstitial lung disease and one with clinically significant cardiac involvement. Participants treated with rapcabtagene autoleucel in Cohort 1 demonstrated rapid and profound B cell depletion following CAR-T expansion. Two participants with >=20 weeks of follow-up demonstrated a >=30% reduction in the mRSS along with stabilization or improvement in pulmonary function and were able to discontinue immunosuppressive therapies. Rapid improvements were noted in patient and physician global assessment and disability index. In all 3 participants with >=4 months of follow-up, circulating CD19 B cells reappeared 90 days post-infusion. Rapcabtagene autoleucel was well tolerated (table 1). All cases of cytokine release syndrome resolved without sequelae. No instances of immune effector cell-associated neurotoxicity syndrome were observed. Adverse events were manageable and aligned with the established safety profile of CAR-T cell therapies. Conclusions Preliminary data from Cohort 1 suggests a favorable safety profile, CAR-T cell expansion, B cell depletion and promising initial efficacy of rapcabtagene autoleucel in severe refractory dcSSc, supporting its continued evaluation. Funding Statement Novartis Pharma AG, Basel, Switzerland.

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