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

作者：Yujing Li, Sujun Li, Xiaojuan Zhao, Jun Sheng, Lei Xue, Georg Schett, Ce Shi, Biliang Hu, Xingbing Wang, Chen Zhu · 发表于：Cell Research · 年份：2025 · DOI：10.1038/s41422-024-01068-2 · 被引用次数：44 · 研究领域：CAR-T cell therapy research、Biosimilars and Bioanalytical Methods、Integrated Circuits and Semiconductor Failure Analysis

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...