Background/Purpose: We have previously shown that CD19 CAR T cell therapy leads to stable drug-free remission of treatment-resistant SLE (1,2). Based on these findings we addressed the question whether disease-specific autoimmunity resolves in a sustainable way in CD19 CAR T cell- treated SLE patients. We also asked the question whether CD19 CAR T cell therapy affects long-term vaccination responses

Methods: Patients with treatment-resistant SLE received a single infusion of 1 million CD19 CAR T cells per kilogram body weight. CAR T cells were manufactured from autologous T cells and transfected with the lentiviral vector MB-CART19.1 (Miltenyi) encoding the CD19 CAR. Immunosuppressive treatment was stopped before CAR T cell infusion. Standard conditioning treatment (1g/m2 cyclophosphamide, 75 mg fludarabine) was done before CAR T cell infusion. SLE disease activity was sequentially monitored over at least one year with a maximum of up to two years. Autoantibodies (reactivities against double stranded (ds) DNA, single stranded (ss) DNA, nucleosomes, secondary necrotic cells, Smith antigen and Ro60 antigen) were measured at baseline, 3 months after CAR T cell therapy and at last follow-up (1-2 years after CAR T cell therapy). In addition, vaccination responses against measles, mumps, rubella, varicella zoster virus (VZV), Epstein Barr virus (EBV), tetanus and pneumococcus (PC) were assessed. All the antibody measurements were done by commercial ELISA. Anti-dsDNA antibodies were additionally measured by radioimmunoassay (RIA).

Results: Between March 2021 June 2023 8 SLE patients received treatment with CD19 CAR T cell therapy. Five patients had a follow up of more than one year post CAR T cell infusion. All 8 patients fulfilled DORIS remission criteria at time of writing the abstract (June 2023), had a SLEDAI-2K equal to zero and were off glucocorticoid therapy and any other immunosuppressive medication. Autoantibodies against dsDNA (4/5), ssDNA (4/5), nucleosomes (5/5), secondary necrotic cells (4/5) and Smith antigen (3/5) disappeared after CD19 CAR T cell therapy with the exception of nucleosome antibody response in one patient and remained negative until the last follow-up (12-24 months after treatment) (Table 1A). Also RIA-based detection of anti-dsDNA antibodies showed sustained seroconversion. Ro60 activity, which was found in one patient, remained stable throughout the observation period but did apparently no impact disease activity. In contrast to autoantibodies, antibody reactivities against measles, mumps, rubella, VZV, EBV, tetanus and PC remained stable 12-24 months after treatment (Table 1B).

Conclusion: CD19 CAR T cells therapy lead to a sustained disappearance of autoantibodies in SLE patients, while vaccination responses remained stable. This observation suggests that the main cellular source of autoantibodies in SLE are CD19+ plasmablasts, which are depleted by CD19 CAR T cells, while antibodies related to vaccination responses appear to predominantly stem from CD19-negative plasma cells. The selective and sustained abrogation of disease specific autoimmunity without affecting vaccination responses provides a favorable combination for the safety and efficacy of CD19 CAR T cell therapy in SLE.

ACR Meeting Abstracts - https://acrabstracts.org/abstract/car-t-cell-therapy-leads-to-long-term-abrogation-of-autoimmunity-in-sle-patients-while-vaccination-responses-are-maintained/