Objective:

To evaluate the efficacy of engineered CAR T cells targeting TNF in a mouse model of rheumatoid arthritis.

Approach:

• Engineering CAR T Cells: CD8-positive T cells were modified with a TNFR1-based chimeric antigen receptor and CRISPR edits to enhance long-term persistence.
• Targeting Mechanism: The CAR T cells were designed to bind and degrade soluble TNF through receptor-mediated endocytosis.
• Experimental Model: The study used human TNF-transgenic mice to assess the therapeutic effects of a single infusion of TNFR1TIF cells.

Key Findings:

• A single infusion of TNFR1TIF cells reduced serum human TNF to near wild-type levels.
• The treatment prevented or treated rheumatoid arthritis-like disease in mice.
• Disease control from a single infusion was comparable to repeated high-dose adalimumab.
• The engineered cells persisted in peripheral blood for up to one year without lymphodepleting preconditioning.

Interpretation:

Limitations:

• The hTNF-transgenic mouse model does not fully represent the heterogeneity of human rheumatoid arthritis.
• Translation to humans would require humanized CAR designs and safety assessments.

Conclusion: