Objective:

To discuss CAR-based immune cell therapies targeting fibroblast-like synoviocytes (FLS) in rheumatoid arthritis (RA) with a focus on safety and selectivity.

Approach:

• Targeting Pathogenic FLS: The review discusses engineered immune cells (CAR-T, CAR-NK, CAR-macrophages) that target FLS-specific antigens, aiming to eliminate or modulate pathogenic FLS.
• Safety-First Roadmap: A 'safety-first' translational roadmap is proposed, incorporating features such as transient CAR expression, safety switches, hypoxia-responsive constructs, and localized delivery.

Key Findings:

• Current RA therapies yield low rates of full remission, with many patients experiencing residual synovitis.
• Pathogenic FLS are key mediators of RA, showing hyperproliferation and resistance to apoptosis.
• Direct targeting of FLS could address limitations of existing therapies and has shown promise in preclinical trials.

Interpretation:

Targeting pathogenic FLS with engineered immune cells could reshape RA treatment by dismantling the inflammation process with precision.

Limitations:

• Existing therapies largely ignore stromal drivers of RA.
• Clinical translation requires careful validation of targets and patient selection.

Conclusion:

The review advocates for innovative CAR-based therapies targeting FLS to improve RA treatment outcomes while prioritizing safety.