Fourth-Generation Chimeric Antigen Receptor T-Cell Therapy is Tolerable and Efficacious in Treatment-Resistant Rheumatoid Arthritis

Rheumatology and Immunology Immunology Life Sciences Medicine
Chimeric Antigen Receptor T-Cell Rheumatoid Arthritis Treatment-Resistant Autoimmune Disease Cell Therapy

Rheumatoid Arthritis (RA) is an autoimmune inflammatory disease characterized by symmetric synovitis, leading to progressive functional disability in patients. Although monoclonal antibody therapies targeting cytokines (e.g., tumor necrosis factor-α, TNFα) and B cells (e.g., CD20-targeted antibody rituximab) have significantly improved RA treatment outcomes in recent years, up to 30% of patients remain unresponsive to multiple immunomodulatory drugs. These patients are referred to as “Difficult-to-Treat (D2T)” RA. To address this issue, researchers have developed a novel autologous fourth-generation CD19-targeted Chimeric Antigen Receptor (CAR) T-cell therapy. This therapy not only targets and eliminates CD19+ B cells but also secretes anti-IL-6 and anti-TNFα antibodies, thereby locally suppressing inflammatory responses.

Source of the Study

The study was conducted by Yujing Li, Sujun Li, Xiaojuan Zhao, and others from the Department of Rheumatology and Immunology at the First Affiliated Hospital of the University of Science and Technology of China, with support from institutions such as Friedrich Alexander University Erlangen-Nuremberg. The findings were published on January 9, 2025, in the journal Cell Research, under the title Fourth-generation chimeric antigen receptor T-cell therapy is tolerable and efficacious in treatment-resistant rheumatoid arthritis.

Research Process and Results

Research Process

  1. Patient Selection and Treatment
    The study enrolled three RA patients who were unresponsive to multiple conventional and biologic treatments. All patients provided informed consent, and the study was approved by the Ethics Committee of the First Affiliated Hospital of the University of Science and Technology of China. Baseline characteristics of the three patients included ages (49, 52, and 56 years), Disease Activity Scores (DAS28-ESR) of 5.57, 5.34, and 5.90, respectively, and all had previously received glucocorticoids and multiple disease-modifying antirheumatic drugs (DMARDs).

  2. CAR-T Cell Preparation and In Vitro Testing
    The researchers developed a novel fourth-generation CAR-T cell that targets CD19 and secretes anti-IL-6 and anti-TNFα antibodies (CD19/αIL-6/αTNFα CAR-T). In vitro experiments confirmed that these CAR-T cells could effectively release anti-IL-6 and anti-TNFα antibodies.

  3. CAR-T Cell Infusion and Monitoring
    The three patients received CD19/αIL-6/αTNFα CAR-T cell infusions. During infusion, patients’ body temperature, heart rate, and respiratory rate remained within normal ranges, with only mild transient tachycardia observed in Patients 1 and 2. No cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS) was observed.

  4. In Vivo CAR-T Cell Expansion and B Cell Depletion
    CAR-T cells rapidly expanded in vivo, peaking on day 9 for Patient 1, day 21 for Patient 2, and day 14 for Patient 3. CD19+ B cells were completely eliminated from peripheral blood within 3 days for Patient 1 and 7 days for Patients 2 and 3.

  5. Clinical Efficacy Evaluation
    After treatment, patients showed significant reductions in tender and swollen joint counts, as well as improvements in Disease Activity Scores (DAS28), Clinical Disease Activity Index (CDAI), and Simplified Disease Activity Index (SDAI). Additionally, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels were significantly reduced.

  6. Long-term Follow-up and Immunoglobulin Level Changes
    Long-term follow-up revealed that although B cells reappeared within 60 to 90 days post-treatment, no RA relapse was observed. Immunoglobulin (IgG, IgA, IgM) levels significantly decreased, indicating the long-term impact of CAR-T cell therapy on the immune system.

Research Results

  1. Good Tolerability
    All patients tolerated the CAR-T cell infusions well, with no serious adverse events reported. The absence of CRS or ICANS indicates the high safety profile of this therapy.

  2. B Cell Depletion and Disease Remission
    CAR-T cells rapidly expanded in vivo and effectively eliminated CD19+ B cells, significantly improving patients’ joint symptoms and disease activity scores. Post-treatment, patients showed marked reductions in tender and swollen joint counts and significant improvements in disease activity scores.

  3. Long-term Efficacy and Immune System Impact
    Despite the reappearance of B cells, no RA relapse was observed. The significant reduction in immunoglobulin levels highlights the long-term effects of CAR-T cell therapy on the immune system.

Conclusions and Significance

This study is the first to apply fourth-generation CAR-T cell therapy to autoimmune diseases, particularly treatment-resistant RA. The results demonstrate that CD19/αIL-6/αTNFα CAR-T cell therapy not only effectively depletes B cells but also locally suppresses inflammatory responses, significantly improving patients’ clinical symptoms and disease activity scores. The success of this therapy provides a new approach for RA treatment, especially for patients with treatment-resistant RA, and holds broad application prospects.

Highlights of the Study

  1. Innovative Therapy
    This study is the first to apply fourth-generation CAR-T cell therapy to RA treatment, combining B cell depletion and local cytokine suppression mechanisms.

  2. Good Tolerability
    All patients tolerated the CAR-T cell infusions well, with no serious adverse events, indicating the high safety profile of this therapy.

  3. Significant Efficacy
    Post-treatment, patients showed significant improvements in joint symptoms and disease activity scores, with effective B cell depletion and local inflammation suppression.

  4. Long-term Efficacy
    Despite the reappearance of B cells, no RA relapse was observed, demonstrating the long-term efficacy of this therapy.

Additional Valuable Information

The study also found that the long-term impact of CAR-T cell therapy on immunoglobulin levels warrants further investigation. Moreover, the success of this therapy provides new insights for the treatment of other autoimmune diseases, highlighting its significant scientific and clinical value.