University Hospital Erlangen, Medicine 3 Erlangen, Germany
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Christina Bergmann1, Fabian Müller2, Janina Auth3, Jule Taubmann4, Michael Aigner5, Dagmar Werner6, Andreas Wirsching7, Johannes Knitza8, Hermina Györfi9, Jörg Distler10, Andreas Mackensen5 and Georg Schett11, 1Department of Internal Medicine 3-Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and University Hospital Erlangen, Erlangen, Germany, 2Friedrich Alexander Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany, 3University Hospital Erlangen, Medicine 3, Erlangen, Germany, 4Department of Internal Medicine 3, Rheumatology and Immunology, Universitätsklinikum Erlangen and Friedrich-Alexander-Universität Erlangen Nürnberg, Erlangen, Germany, 5Department of Internal Medicine 5, Hematology and Oncology, Universitätsklinikum Erlangen and Friedrich-Alexander-Universität Erlangen Nürnberg, Erlangen, Germany, 6FAU Erlangen-Nürnberg, Erlangen, Germany, 7University Hospital Erlangen, Department of Internal Medicine 3, Erlangen, Germany, 8Department of Internal Medicine 3 Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg, University Hospital Erlangen, Erlangen, Germany, 9Clinic for Rheumatology University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University, Düsseldorf, Germany; Hiller Research Center, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University, Düsseldorf, Germany, 10Department of Internal Medicine 3 – Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and University Hospital Erlangen, Erlangen, Germany; Deutsches Zentrum für Immuntherapie, Friedrich Alexander University Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany, 11Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
Background/Purpose: CD19-targeting CAR-T-cells showed remarkable improvements in autoimmune diseases including refractory lupus erythematodes (1,2) and inflammatory myopathy (3). Moreover, first data of a patient with diffuse Systemic Sclerosis (SSc) were recently reported (4). Here we present 6 months follow up data of the first three patients with severe diffuse SSc who received CAR-T-cell treatment.
Methods: T-cells were acquired by peripheral blood apheresis and transfected with a lentiviral vector encoding a CAR against CD19 (Miltenyi Biotec) using the CliniMacs Prodigy system (Miltenyi Biotec). Infusion of CAR-T-cells was performed upon lymphodepletion with fludarabine (25 mg/m2 on days -5, -4, -3) and cyclophosphamide (1g/m2 on day -3, 50% dose reduction in patient 3 due to renal insufficiency) as single infusion. Immunosuppression was stopped before CAR-T-cell infusion. Outcomes were assessed before baseline and 6 months after CAR-T-cell infusion.
Results: Three SSc patients were treated with CAR-T-cells with a follow up of 6 months: patient 1 (male, baseline data: 60 yrs, disease duration 2 years (first non-Raynaud symptom), mRSS 24, myocardial- and lung fibrosis, anti RNAP3-antibodies), patient 2: male, 37 yrs, mRSS 27, disease duration 1.5 yrs, lung- and myocardial fibrosis, digital ulcerations (DU), anti-Scl70 antibodies) and patient 3 (female,38 yrs, disease duration 1.5 yrs, mRSS 32, scleroderma renal crisis, DU, anti-Scl70 antibodies). All patients had failed state of the art SSc treatments. The CAR-T-cell procedure was well tolerated: Patient 1 developed mild CRS (grade I; fever) and an episode of respiratory tract infection three months after CAR-T infusion, treated outpatient with antibiotics. B-cells were completely absent in peripheral blood within 7 days after CAR-T cells administration in all patients. ANA titres were reduced by 10-fold in patients 2 and 3, patient 1 converted to negative ANA status within 3 months and anti-RNAP III antibodies turned negative. mRSS improved in all three patients until six-months follow up (median 6 points (5-7)). 2 patients suffered from multiple digital ulcerations despite bosentan- treatment before CAR-T cells, which were no longer detectable on follow up. All patients reported improvement of hand function (median reduction of Cochin Hand function scale of 8 points (8-20). Improvement of HAQ-DI ranged from 0.5 to 1.38 points and of EUSTAR activity from 3.62 to 4.37 points. Lung function parameters remained stable in patients 1 and 3 and improved in patient 2 (FVC increase by 390 ml (8%)). Myocardial 68Ga-FAPI-04-uptake declined in patients 1 and 2 by 30% and 35% respectively. B-cells recurred after 84 days in patient 1 and 2 without signs of disease activity.
Conclusion: These data on the first three SSc patients receiving CD19 CAR-T cell treatment show that the procedure is well tolerated and can lead to stabilization of SSc disease activity without additional immunosuppression on 6 months follow up.
C. Bergmann: Boehringer-Ingelheim, 2, 5, Janssen, 2; F. Müller: AbbVie, 6, AstraZeneca, 1, 5, 6, Bristol Myers Squibb, 1, 6, Janssen, 6, KITE, 1, 6, Miltenyi Biomedicine, 1, 6, Novartis, 1, 6, Sobi, 6; J. Auth: None; J. Taubmann: None; M. Aigner: Kosmas Therapuetics, 8, Kyverna, 5, Miltenyi Biomedicine, 2, 7, Miltenyi Biotec, 6; D. Werner: None; A. Wirsching: None; J. Knitza: None; H. Györfi: Boehringer-Ingelheim, 6; J. Distler: None; A. Mackensen: BioNTech, 1, Bristol-Myers Squibb(BMS), 1, KITE/Gilead, 1, 6, Kyverna, 5, Miltenyi Biotech, 5; G. Schett: None.