A research team at Tsinghua University announced on June 22 the development of engineered CAR-T cells that may offer a new approach to treating rheumatoid arthritis. The study, published in hLife, details how these TNFR1TIF cells capture and degrade soluble tumor necrosis factor (TNF), acting as a self-renewing, living cellular drug.
Currently, approximately 18 million people live with rheumatoid arthritis and rely on lifelong injections of biologic drugs such as adalimumab. These treatments require dosing every two weeks and can lead to anti-drug antibody formation over time, which reduces their effectiveness and increases infection risks. While targeted protein degradation technologies like LYTACs and KineTACs have emerged as alternatives, they still depend on repeated dosing.
Led by Professor Min Peng, the Tsinghua University team engineered TNFR1TIF cells using receptor-mediated endocytosis to specifically target soluble TNF. In tests with human TNF-transgenic mice, a single infusion of these cells prevented and treated all stages of rheumatoid arthritis without the need for redosing or risk of anti-drug antibodies. The efficacy matched that of repeated high-dose adalimumab injections.
The researchers constructed the TNFR1 CAR by fusing mouse TNFR1 ectodomain with CD28 co-stimulatory and CD3ζ signaling domains. To enable robust expansion without lymphodepleting preconditioning—a typical barrier in conventional CAR-T therapies—they used CRISPR-Cas9 to co-delete Bcor and Zc3h12avia genes. The modified cells persisted for over one year in immunocompetent mice only when TNF was present, with no observed disruption to immune function or organ integrity during twelve months of monitoring.
A pharmacological safety switch using an anti-Thy1.1 depleting antibody allowed efficient elimination of the engineered cells in vivo. The platform is considered broadly applicable for other cytokines involved in disease processes such as IL-1β, IL-4, IL-17, or even amyloid-β aggregates found in Alzheimer's disease.
The work was conducted at several institutions within Tsinghua University in Beijing alongside Shanxi Medical University and supported by national research grants.
