POS0062 SAFETY AND PRELIMINARY EFFICACY OF CD19 CAR T-CELL TREATMENT IN RHEUMATIC DISEASE – DATA FROM THE PHASE I/II CASTLE BASKET STUDY

Background: Systemic autoimmune diseases are based on a deep perturbation of immune homeostasis leading to the formation of autoreactive B-cells and autoantibodies. 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 [1-3]. Objectives: To assess the safety and preliminary efficacy of CD19-CAR T-cell therapy in autoimmune diseases in a controlled clinical study. Methods: CASTLE (CAR T-cells in systemic B cell-mediated autoimmune disease) is a phase I/II basket study (sponsor: Miltenyi Biomedicine, Bergisch Gladbach, Germany) that assesses the safety (1° endpoint) and preliminary efficacy (2° endpoint) of CD19-CAR T-cell therapy in severe refractory systemic lupus erythematosus (SLE), idiopathic inflammatory myositis (IIM) and systemic sclerosis (SSc). CASTLE consists of a first phase with 8 patients, which is followed by a second phase with 16 patients, given that toxicity is acceptable (<5 toxicity events such as cytokine-release syndrome (CRS) > grade 2, immune effector cell-associated neurotoxicity syndrome (ICANS) > grade 2, neutropenia/leukocytopenia > grade 2 of more than 28 days and organ toxicity > grade 2) and if 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 1x10 6 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 response. Data-cut-off was December 15 th 2024. Results: This unplanned analysis to update the community comprises 20 patients (8 SLE, 8 SSc, 4 IIM) from 1st and 2nd phase. Median [IQR] age was 39.5 [27; 54.25] years, median disease duration 3.75 [1; 6] years, median follow up time 7 [5.5; 12.25] months. CAR-T cells expanded in all patients with a median maximum of 146 [83; 360] cells/microliter (N=20). Median B cell depletion lasted for 84 [83; 360) days (N=12 with B-cell repletion). Circulating CAR T-cells were lower than 1 cell/microliter at a median of 56 [35; 58] days and not detectable after a median of 83 [56; 105] days (both N=16). In the 20 patients, no higher-grade CRS (grade 3 or 4) was observed (grade 1: N=13; grade 2: N=1) and no ICANS occurred. Early neutropenia of any grade was seen in 19 patients (95%) due to lymphodepletion therapy, while only 4 patients showed a late grade 3/4 neutropenia. All 4 were SLE patients. Bone marrow biopsies were performed in 2 patients without signs of blasts or dysplasia. All early and late neutropenia events resolved. Severe infections, defined by hospitalization, were observed in 3 patients (1 SLE, 1 IIM, 1 SSc), all of them were pneumonias and none had to be treated on ICU. Efficacy data at week 24 were available from 15/20 patients with 6-months follow-up. All 7 SLE patients achieved DORIS remission, both IIM patients achieved ACR moderate/major response and all 6 SSc patients showed no worsening of lung function and improved in skin scores. Furthermore, all patients remained off any immunosuppressive drugs and glucocorticoids for their underlying disease after CAR T-cell treatment. Conclusion: These data underline the safety of CD19-CAR T-cell therapy in the treatment of autoimmune disease. No higher-grade CRS or ICANS and no sustained myelotoxicity were observed. Also, the preliminary efficacy data met the expectations in SLE, IIM and SSc. REFERENCES: [1] Müller F, Taubmann J, Bucci L, et al. CD19 CAR T-Cell Therapy in Autoimmune Disease - A Case Series with Follow-up. N Engl J Med . 2024; 390:687-700. [2] Isaacs JD. CAR T Cells - A New Horizon for Autoimmunity?. N Engl J Med . 2024; 390:758-759. [3] Tur C, Eckstein M, Velden J, et al. CD19-CAR T-cell therapy induces deep tissue depletion of B cells. Ann Rheum Dis . Published online September 11, 2024. doi:10.1136/ard-2024-226142. Acknowledgements: NIL . Disclosure of Interests: Melanie Hagen: None declared, Andreas Wirsching: None declared, Fabian Müller Speakers Bureau: AstraZeneca, Abbvie, Beigene, BMS, Janssen, Kite/Gilead, Miltenyi, Novartis, Sobi, Taketa, Advisory Board: AstraZeneca, BMS, CRISPR Therapeutics, Janssen, Kite/Gilead, Miltenyi, Novartis, Sobi, Research Funding: MedImmune/AstraZeneca, Kite/Gilead, BMS, Soraya Kharboutli: None declared, Christina Bergmann Kyverna (travel grant), Sebastian Boeltz: None declared, Jule Taubmann: None declared, Carlo Tur: None declared, Laura Bucci: None declared, Simon Völkl: None declared, Michael Aigner Miltenyi (speaker honoraria), Miltenyi (consulting fees), Kyverna (research support), Sascha Kretschmann: None declared, Silvia Spörl: None declared, Ingrid Vasova: None declared, Daniel Aletaha: None declared, Hans Kiener: None declared, Gerlando Natalello: None declared, Franco Locatelli: None declared, Maria Antonietta D' Agostino: None declared, Aline Bozec: None declared, Linda Hanssens Miltenyi Biomedicine, Ricardo Grieshaber-Bouyer Kyverna (research support), Andreas Mackensen speaker honoraria: BMS, Century Therapeutics Celgene, Kyverna Gilead, Janssen, Miltenyi, and Novartis, consulting fees: BMS, Century Therapeutics Celgene, Kyverna Gilead, Janssen, Miltenyi, and Novartis, Georg Schett speaker honoraria: BMS, Cabaletta, Kyverna, Janssen, Miltenyi, and Novartis. © The Authors 2025. This abstract is an open access article published in Annals of Rheumatic Diseases under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Neither EULAR nor the publisher make any representation as to the accuracy of the content. The authors are solely responsible for the content in their abstract including accuracy of the facts, statements, results, conclusion, citing resources etc.