Fourth-generation chimeric antigen receptor T-cell therapy is tolerable and efficacious in treatment-resistant rheumatoid arthritis

Abstract

Rheumatoid arthritis (RA) is an autoimmune inflammatory disease characterized by symmetric synovial inflammation leading to progressive disability. 1 Treatment of RA has been revolutionized by the development of monoclonal antibodies against cytokines (e.g., tumor necrosis factor-α (TNFα) and interleukin-6 (IL-6)) as well as B-cells (e.g., CD20-targeted antibody rituximab), resulting in better disease control. 2 However, up to 30% of RA patients still escape therapeutic responses despite several cycles of immunomodulatory drugs. 3 Such patients are referred to as “difficult-to-treat (D2T)” RA according to European Alliance of Associations for Rheumatology (EULAR) definition. 3 Here, we report on the efficacy and safety of a new, autologous, fourth-generation CD19-targeted chimeric antigen receptor (CAR) T-cells that secrete antibodies against IL-6 and TNFα (CD19/aIL-6/aTNFα) in treating D2T RA (Fig. 1a, b ). Fig. 1: Clinical safety and efficacy of CD19/aIL-6/aTNFα CAR T-cells in RA. a Design of chimeric antigen receptor (CAR) construct and sequences of anti-IL-6 single chain variable fragments (scFv) and anti-TNFα scFv. b Schematic illustration of CAR T-cells depleting CD19 B cells and secreting scFv of immunoglobulins against IL-6 and TNFα (CD19/aIL-6/aTNFα CAR T-cells). c Body temperature, heart rate and respiratory rate taken at the same time of the day after treatment with CAR T-cells. d Numbers of circulating CD19 + B cells in the patients’ peripheral blood. e Effects of CAR T-cells on tender and swollen joint counts (TJC, SJC). f Physician global assessment of disease activity using visual analog scale (VAS). g Effects of erythrocyte sedimentation rates (ESR) and C-reactive protein (CRP) levels. Disease activity scores-28 (DAS28) based on ESR and CRP ( h ) and clinical disease activity index (CDAI) and simplified disease activity index (SDAI) ( i ). j Serum levels of rheumatoid factor (RF) and antibodies against cyclic citrullinated peptide (CCP) at baseline and during 6-month follow-up. k Representative images of ultrasound Power Doppler (PD) signal (arrowheads) in the knee joint before and 3 months after CAR T-cell therapy (patient 2). Scale bars, 1 cm. l Representative MRI scans showing improved synovitis (arrowheads) of the hands and metacarpophalangeal joint (MCP) at baseline and 3 months after CAR T-cell treatment (patient 2). Scale bars, 1 cm. m Effects of CAR T-cell therapy on serum levels of immunoglobulins G (IgG), A (IgA), and M (IgM). Dotted lines, cut-off values. Full size image

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