Background/Purpose: Engineered T cells expressing a chimeric antigen receptor (CAR) binding CD19 are powerful tools to deplete B-cells, representing an attractive therapy for severe autoimmune diseases, such as systemic lupus erythematosus (SLE), idiopathic inflammatory myositis (IIM) and systemic sclerosis (SSc). Case reports and case series have supported the feasibility of CAR T-cell therapy in SLE, IIM and SSc showing preliminary safety and efficacy (1-3). Clinical data from phase I/II studies investigating the potential of CAR T-cell therapy in autoimmune disease are underway. Their results will provide further insights in the therapeutic role of CAR T-cells in these diseases.

Methods: CASTLE is a phase I/II basket study (Miltenyi Biomedicine, EudraCT-Nr.2022-001366-35) assessing the safety (primary endpoint) and efficacy (secondary endpoint) of 1×106 autologous CD19 CAR T-cells (MB-CART19.1) /kg BW after lymphodepleting chemotherapy with Fludarabin/Cyclophosphamide in patients with SLE, IIM and SSc. Previous immunosuppressants/immunomodulatory therapies were stopped at the time of lymphodepletion. 8 patients were recruited in a first safety phase, followed by additional 16 patients in the second phase. Dose limiting toxicity (DLT) and consecutive stopping rules were grade 3/4 cytokine release syndrome (CRS), grade 3/4 immune cell-associated neurotoxicity syndrome (ICANS), clinically relevant neutropenia or thrombopenia lasting >4 weeks or grade 3/4 organ toxicity within 4 weeks after IMP-infusion. Efficacy was assessed by B-cell depletion and CAR T-cell expansion. Clinical responses were defined by DORIS remission in SLE, ACR/EULAR Moderate or Major Response in IIM, and no progression of interstitial lung disease in SSc.

Results: In total, 28 patients were screened, 24 patients were enrolled (17 women, 7 men) with a median (IQR) age of 39 [26; 53] years. 10 patients had SLE, 9 SSc and 5 IIM with a median (IQR) number of 4 [3; 6] previous immunosuppressive treatments. 18/24 developed mild CRS (17 grade 1; 1 grade 2). No higher-grade CRS and no ICANS occurred. No clinically relevant neutropenia or thrombopenia >4 weeks were recorded. One grade 3 organ toxicity due to renal thrombotic microangiopathy in conjunction with CMV infection occured. Local immune effector cell-associated toxicity syndrome (LICATS (4)) was reported in 88% of patients with grade 1/2 in the vast majority of patients. Median (IQR) CAR T-cell expansion was 140 [82; 360] cell/microliter, median (IQR) time of CAR T-cell presence was 83 [56; 113] days. B-cells were depleted in all patients. Six-month efficacy data were available in 19/24 patients at data cut-off of May 12, 2025: All 7 SLE patients were in DORIS remission, all 8 SSc showed no disease progression and all 4 IIM patients met ACR/EULAR Moderate or Major Response. In addition, clinical responses were also observed in the residual 5 patients, in whom follow-up time was still less then 6 months. All 24 patients stopped any immunosuppressive medication.

Conclusion: The CASTLE study met its primary safety and secondary efficacy endpoint. The data confirm favorable safety and high efficacy of MB-CART19.1 in the setting of a controlled phase I/II study in patients with autoimmune disease.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/safety-and-efficacy-of-autologous-cd19-car-t-cell-therapy-in-patients-with-autoimmune-disease-data-from-the-castle-phase-i-ii-basket-study/