Georg Schett1, Sebastian Böltz2, Fabian Müller2, Arnd Kleyer3, Simon Völkl2, Michael Aigner2, Regina Gary2, Sascha Kretschmann2, David Simon3, Soraya Kharboutli2, Dimitrios mougiakakos4, Gerhard Kroenke3 and Andreas Mackensen2, 1Universitätsklinikum Erlangen, Erlangen, Germany, 2FAU Erlangen-Nürnberg, Erlangen, Germany, 3Department of Internal Medicine 3 – Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg and Universitätsklinikum Erlangen, 91054 Erlangen, Germany; Deutsches Zentrum Immuntherapie, Friedrich-Alexander-UniversityErlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany, 4University of Magdeburg, Magdeburg, Germany
Background/Purpose: Chimeric antigen receptor (CAR) T cells have been used to treat refractory forms of B cell and plasma cell malignancies. B cells are also appreciated as major players in Systemic lupus erythematosus (SLE). Monoclonal antibodies against B cells have been used to treat SLE, however they do not completely deplete B cells in the tissues. We therefore examined whether CAR T cells targeting B cells may allow deep B cell depletion and remission in patients with treatment-refractory SLE.
Methods: T cells were enriched from a peripheral blood apheresis product and stable transfected with a lentiviral vector encoding a CAR against CD19 (Miltenyi Biotec) using the CliniMacs Prodigy system (Miltenyi Biotec). After conditioning, patients received 1x106 CD19-CAR-T cells/kg body weight as single infusion. All SLE treatments were stopped before CAR-T cell administration. Tolerability was assessed by monitoring for Cytokine-release syndrome (CRS), CAR T-cell-related encephalopathy syndrome (CRES) and infections. Preliminary efficacy was assessed by reaching Lupus Low Disease Activity State, DORIS remission criteria, seroconversion and sustained cessation of all SLE-specific treatments. In addition, BCR sequencing was performed at baseline and after re-appearance of B cells.
Results: Five SLE patients were treated with CAR-T cells with a follow up of 14 months (patient 1, female aged 20, SLEDAI-2K: 16), 11 months (patient 2, male aged 22; SLEDAI-2K:16), 6 months (patient 3, female aged 22; SLEDAI 2K: 10), 5 month (patient 4; female aged 24; SLEDAI-2K: 8) and 3 months (patient 5; female aged 18; SLEDAI-2K: 9). All patients had active severe SLE with failure of standard treatments and had active kidney disease with histology proven glomerulonephritis and proteinuria > 1 g/24 hours. No infection and no CRES occurred. Three patients developed mild CRS (grade I; fever), which rapidly ceased after novaminsulfone and in one patients tocilizumab. B cells were completely absent within the peripheral blood from day 2 after CAR-T cells administration. All patients experienced sustained drug-free remission (patient 1 and 3-5:SLEDAI-2K=0, patient 2: SLEDAI-2K=2) meeting Lupus Low Disease Activity State (LLDAS) and DORIS remission criteria of SLE. Anti-dsDNA antibodies seroconverted and in the two patients with longer follow up (patients 1 and 2) also ANA became negative. All five patients remained off immunosuppressive drugs including glucocorticoids. B cells returned after mean±SD of126±48 days with no signs of flare or recurrence of autoantibodies. Preliminary analysis of B cell receptor repertoires at baseline and follow-up showed loss of initially expanded clonotypes, even distribution of BCR clonotypes and predominantly use of IgD and IgM heavy chains, suggesting rebooting of the B cell system.
Conclusion: These data on the first five SLE patients receiving CD19 CAR-T cell treatment show that the procedure is well tolerated and can lead to long-term drug-free remission of severe treatment-refractory SLE.
Disclosures: G. Schett, None; S. Böltz, None; F. Müller, None; A. Kleyer, None; S. Völkl, None; M. Aigner, None; R. Gary, None; S. Kretschmann, None; D. Simon, None; S. Kharboutli, None; D. mougiakakos, None; G. Kroenke, None; A. Mackensen, None.
