Background/Purpose:

Systemic autoimmune diseases are based on an aberrant activation of B cells. Autologous CD19 chimeric antigen receptor (CAR) T cells allow deep depletion of B cells in humans and represent a new possibility to treat autoimmune disease. Previous observations have suggested that a single infusion of CD19-CAR-T cells is not only well tolerated in patients with SLE and other autoimmune diseases but also induces sustained drug-free remission. However, safety and efficacy of CD19-CAR-T cell therapy in autoimmune disease has to be demonstrated in controlled clinical studies.

Methods: CASTLE (CAR-T cells in systemic B cell-mediated autoimmune disease) is a phase I/II basket study that assesses the safety (1° endpoint) and preliminary efficacy (2° endpoint) of CD19-CAR-T therapy in progressive, refractory systemic lupus erythematosus (SLE), idiopathic inflammatory myositis (IIM) and systemic sclerosis (SSc). CASTLE consists of a first phase with 8 patients, followed by a second phase with 16 patients, if toxicity is acceptable (< 5 toxicity events such as cytokine-release syndrome (CRS) > grade 2, immune effector cell-associated neurotoxicity syndrome (ICANS) > grade 2, grade III/IV neutropenia/leukocytopenia >28 days and organ toxicity >2) and efficacy is good (≥ 4 responders). Standard cyclophosphamide/fludarabine conditioning therapy was followed by a single infusion of an advanced therapy medicinal product (MB-CART19.1) containing 1×10⁶ CD19-CAR-T cells/kg body weight. Safety was assessed by recording CRS, ICANS, myelotoxicity and organ toxicity during the first 28 days. Preliminary efficacy was assessed by assessing B cell depletion, CAR-T cell expansion and clinical responses.

Results: This interim analysis comprises 11 patients (6 SLE, 3 SSc, 2 IIM) from 1^st phase and early 2^nd phase. Median age was 38 years (20-81), median disease duration 3 years (0.5-13.5), median follow up time 6 months (1-9). From all patients, toxicity data, B cell depletion and CAR-T cell expansion data were available, while clinical efficacy data were available from 9/11 patients with sufficiently long follow-up (3 months). No higher-grade CRS (grade 3 or 4) was observed (grade 0: N=4; grade 1: N=6; grade 2: N=1). No ICANS, no myelotoxicity occurred. CAR-T cells expanded in all patients. Among 9 patients (6 SLE, 2 SSc, 1 IIM) that had sufficiently long follow-up (≥ 3 months), all 6 SLE patients achieved DORIS remission, the one IIM patient achieved ACR Moderate/Major response and both SSc patients showed no worsening of lung function (SSc) and improvement in skin scores. Furthermore, all patients could successfully stop glucocorticoids and immunosuppressive drugs after CAR-T cell infusion. Overall, the predefined endpoints required to fulfill the first phase (N=8 patients) of CASTLE (< 5 toxicity events; ≥ 4 responders) were met and the 2^nd phase of CASTLE started, 3 additional patients were included into the 2^nd phase of CASTLE.

Conclusion:

These data underline the safety of CD19-CAR-T therapy in the treatment of autoimmune disease. No higher-grade CRS or ICANS and no myelotoxicity was observed. Also, the preliminary efficacy data met the expectations in SLE, IIM and SSc.
References: Mueller F et al. N Engl J Med 2024; 390:687-700

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/safety-and-preliminary-efficacy-of-cd19-car-t-cell-treatment-in-rheumatic-disease-data-from-the-first-part-of-the-phase-i-ii-castle-basket-study/