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 1×106 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.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/car-t-cell-treatment-of-refractory-systemic-lupus-erythematosus/