1750: 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
No financial relationships with ineligible companies to disclose
Georg Schett1, Fabian Müller2, Melanie Hagen3, Andreas Wirsching3, Daniela Bohr4, Christina Bergmann5, Carlo Tur3, Simon Völkl6, Michael Aigner7, Sascha Kretschmann7, Silvia Spoerl7, Soraya Kharboutli7, Ingrid Vasova7, Daniel Aletaha8, Hans Kiener9, Gerlando Natalello10, Franco Locatelli11, Maria Antonietta D´Agostino12, Aline Bozec3, Ricardo Grieshaber-Bouyer13 and Andreas MAckensen14, 1Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany, 2Department of Medicine 5 - Hematology and Oncology, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU) and Uniklinikum Erlangen, Erlangen, Germany, 3Department of Medicine 3 - Rheumatology and Immunology, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg and Uniklinikum Erlangen, Erlangen, Bayern, Germany, 4Department of Internal Medicine 3 - Rheumatology and Immunology, Friedrich-Alexander University (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany, Deutsches Zentrum für Immuntherapie (DZI), Friedrich Alexander University Erlangen-Nuremberg and Universitätsklinikum Erlangen, Erlangen, Germany, Erlangen, Germany, 5Department Internal Medicine III, Friedrich-Alexander-University (FAU) Erlangen-Nurnber, Frankfurt, Germany, 6Department of Medicine 5 - Hematology and Oncology, Friedrich-Alexander-Universität Erlangen-Nürnberg and University Hospital Erlangen, Erlangen, Bayern, Germany, 7Department of Medicine 5 - Hematology and Oncology, Friedrich-Alexander-Universität Erlangen-Nürnberg and University Hospital Erlangen, Erlangen, Germany, 8Department of Medicine III, Division of Rheumatology, Medical University of Vienna, Wien, Austria, 9Division of Rheumatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria, Vienna, Austria, 10Division of Rheumatology - Catholic University of the Sacred Heart, Fondazione Policlinico Universitario Agostino Gemelli, Rome, Rome, Italy, 11IRCCS Ospedale Pediatrico Bambino Gesù, Rome, Italy, 12Catholic University of Sacred Heart, Rome, Italy, Rome, Italy, 13Department of Medicine 3 - Rheumatology and Immunology, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg and Uniklinikum Erlangen, Erlangen, Germany, 14Department of Medicine 5 - Hematology and Oncology, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU) and Uniklinikum Erlangen, Erlangen, Bayern, Germany 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 patientswith 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 1x106 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 1st phase and early 2nd 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 2nd phase of CASTLE started, 3 additional patients were included into the 2nd 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
Table 1. Interims analysis of safety and efficacy of the CASTLE trial.
G. Schett: Bristol-Myers Squibb(BMS), 6, Cabaletta, 6, Janssen, 6, Kyverna Therapeutics, 6, Novartis, 6; F. Müller: AstraZeneca, 2, 5, 6, BeiGene, 2, 6, Bristol-Myers Squibb(BMS), 2, 6, Janssen, 2, 6, Kite/Gilead, 1, 5, 6, 12, Travel, Miltenyi, 2, 6, Novartis, 2, 6, Sobi, 2, 6, Takeda, 2, 6; M. Hagen: None; A. Wirsching: None; D. Bohr: None; C. Bergmann: Boehringer-Ingelheim, 2, 5, Janssen, 2, Kyverna Therapeutics, 5; C. Tur: None; S. Völkl: None; M. Aigner: None; S. Kretschmann: None; S. Spoerl: None; S. Kharboutli: None; I. Vasova: None; D. Aletaha: AbbVie, 2, 5, 6, Galapagos, 2, 5, 6, Gilead, 2, 5, 6, Janssen, 2, 5, 6, Lilly, 2, 5, 6, Merck, 2, 5, 6, Novartis, 2, 5, 6; H. Kiener: None; G. Natalello: None; F. Locatelli: None; M. D´Agostino: None; A. Bozec: None; R. Grieshaber-Bouyer: Bristol-Myers Squibb(BMS), 6, Kyverna Therapeutics, Inc., 5; A. MAckensen: Bristol-Myers Squibb(BMS), 1, 2, 6, Celgene, 1, 2, 6, Century Therapeutics, 1, Gilead/Kite, 1, 2, 6, Ixaka, 1, Kyverna Therapeutics, Inc., 1, Miltenyi Biomedicine, 1, 2, 6, Novartis, 1, 2, 6.