Anti-CD19 CAR T cell therapy for refractory systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a severe autoimmune disease that predominantly affects young women. SLE is characterized by the formation of autoantibodies and immune complex–mediated inflammation and organ damage. Although autoreactive B cells play a key role in the pathogenesis of SLE, B-cell depletion by antibodies has only limited therapeutic efficacy. This paradox has been attributed to the inaccessibility and persistence of autoreactive B cells within lymphatic organs and inflamed tissues or the pathologic role of CD20-negative plasma cells, which may act as an additional source of autoantibodies in patients with SLE. Chimeric antigen receptor (CAR)–modified T cells that have been genetically engineered to recognize CD19 and other B-cell surface antigens have emerged as a powerful tool for the treatment of relapsed or refractory B-cell cancers. This technological breakthrough, together with recent convincing data on the role of B cells in disease pathogenesis derived from preclinical lupus models, provides a rationale for the use of CAR T-cell therapies in patients with SLE.

We report here on the use of autologous CD19 CAR T cells in the treatment of an autoimmune disease. A 20-year-old woman with severe and refractory SLE presented with active lupus nephritis (World Health Organization class IIIA, indicating focal proliferative disease with active lesions), nephrotic syndrome, pericarditis, pleurisy, rash, arthritis, and a history of Libman–Sacks endocarditis. Previous treatments with hydroxychloroquine, high-dose glucocorticoids, cyclophosphamide, mycophenolate mofetil, and tacrolimus, as well as the B-cell–targeting therapies belimumab and rituximab, did not control symptoms, deplete B cells, or abrogate autoimmunity (Fig. S1 in the Supplementary Appendix, available with the full text of this letter at NEJM.org). All the treatments were stopped before the planned CAR T-cell infusion, and only low-dose prednisolone was administered. CD19 CAR T cells were produced by lentiviral transduction of autologous fresh leukapheresis in the closed automated CliniMACS Prodigy system (Supplementary Methods section in the Supplementary Appendix). After preparatory lymphodepletion with fludarabine at a dose of 25 mg per square meter of body-surface area per day on days −5, −4, and −3 and cyclophosphamide at a dose of 1000 mg per square meter on day −3, an infusion of 1.1×106 CD19 CAR T cells per kilogram of body weight (ratio of CD4+ to CD8+ T cells, 3:1) was administered on day 0.

reference: https://www.nejm.org/doi/full/10.1056/NEJMc2107725