CD19-Targeted CAR-T Cells in Refractory Systemic Lupus Erythematosus: Safety, Efficacy, and Mechanistic Insights from the First Five Patients

Background: Systemic lupus erythematosus (SLE) is an auto-immune disease that is based on dysregulation of the adaptive immune system, autoantibody production and immune complex-mediated tissue damage. While treatment of SLE has substantially improved, a subset of patients experiences severe progressive disease despite T- and B-cell targeted therapy. Aim: For patients with refractory SLE, we aimed to achieve deep depletion of B cells using autologous CD19-CAR T cells with the goal of achieving an immunological reset and drug free remission. Methods: Five patients (4 women, 1 men) with SLE refractory to several immune-suppressive drugs including pulsed steroids, hydroxychloroquine, mycophenolate, cyclophosphamide, intravenous immunoglobulins, rituximab, and belimumab were treated with CD19 CAR T cells in a compassionate use program. Mean patient age was 21.8 ± 2.3 years, mean disease duration was 4.6 ± 3.0 years and mean SLE disease activity index (SLEDAI) was 11.8±3.8. Autologous T cells were transduced with a lentiviral anti-CD19 CAR vector composed of the FMC63 scFv, a CD8-derived hinge region, TNFRSF19-derived transmembrane domain, CD3ζ intracellular domain, and 4-1BB co-stimulatory domain and expanded within the local GMP facility utilizing the closed automated CliniMACS Prodigy® system (Miltenyi Biotec, Bergisch Gladbach, Germany). CAR T cells were re-infused at a dose of 1x106 CAR T cells/kg body weight after lymphodepletion with fludarabine/ cyclophosphamide. All SLE treatments with the exception of low dose prednisolone was stopped before CAR-T cell administration. After CAR-T cell treatment, no other immune-modulatory or immune-suppressive treatment was given. Tolerability was assessed following international guidelines. Results: Despite long-lasting high dose steroid treatment, sufficient numbers of CD19 CAR-T cells could be generated from 5/5 SLE patients. Lymphodepletion led to expected reduction of white blood cells. Following lymphodepletion, CAR T cells expanded in vivo with a peak on day 9 and a deep depletion of B cells was achieved in all patients. Bone marrow toxicity towards non-B cells was short and all patients recovered neutrophils (>500/nL) before day 14 post CAR T cells. Only mild CRS of °I occurred in all five patients. One patient received a single dose of tocilizumab due to persisting fever >24 hours. There were no ICANS, no CRS of any organ, and no infections. Remission of SLE according to DORIS criteria was achieved in all 5 patients after 3 months and the mean (±SD) SLEDAI score after 3 months was 0.4±0.9. Laboratory parameters normalized in all SLE patients after CAR-T transfer including seroconversion of anti-dsDNA antibodies and all patients were free of immune-suppressive drugs by month 3. One patient presented with proteinuria at month 4. Kidney biopsy as well as serum diagnostics showed no signs of SLE. After a steroid pulse, proteinuria went back to normal. Despite reconstitution of B cells no relapse of SLE was observed in the follow up of any of the patients which are now 17, 12, 8, 7, and 5 months after CAR T cell therapy. Reappearing B cells were naïve and showed non-class switched B cell receptors. While pre-existing vaccine-specific antibodies towards measles or VZV persisted, several auto-reactive antibodies were abrogated. Quality of life was poor at decision to treatment and improved substantially at month three. Improvement was mostly driven by abrogation of joint pain and of fatigue. Conclusions: Taken together, the preliminary data from this pilot study show that CD19 CAR T-cell therapy is very well tolerated in patients with a non-malignant B cell derived autoimmune disease and induce rapid remission of severe refractory SLE. Longer follow-up and higher patient numbers from controlled clinical trials are needed to confirm these promising results.