Engineered CAR-T Cells Offer One-Shot Remission in Rheumatoid Arthritis, Preclinical Study Shows
Key Insights
Tsinghua University researchers developed TNFR1TIF (search) cells, engineered CAR-T cells that capture and degrade soluble TNF (search) through receptor-mediated endocytosis, functioning as a self-renewing living drug.
A single infusion prevented and treated all stages of RA in human TNF (search)-transgenic mice, matching the efficacy of repeated high-dose adalimumab without redosing or anti-drug antibody risk.
CRISPR-Cas9 co-deletion of Bcor and Zc3h12a enabled robust expansion and over one-year persistence in fully immunocompetent mice without lymphodepleting preconditioning.
For the 18 million people living with rheumatoid arthritis (search) (RA), disease management currently means a lifetime of injections—a reality that new research from Tsinghua University may soon begin to change. A research team led by Professor Min Peng has developed engineered CAR-T cells, termed TNFR1TIF (search) cells, that specifically capture and degrade soluble tumor necrosis factor (TNF (search)) through receptor-mediated endocytosis, functioning as a self-renewing, living cellular drug. Published in hLife, the study demonstrates that a single infusion of these cells prevented and treated all stages of RA in human TNF-transgenic mice, matching the efficacy of repeated high-dose adalimumab—without redosing or anti-drug antibody (ADA) risk.
A Paradigm Shift in CAR-T Targeting
Current first-line biologics targeting TNF (search)—including adalimumab (Humira), long among the world's best-selling drugs—require injections every two weeks, potentially for decades. Prolonged use drives ADA formation in many patients, eroding therapeutic benefit and causing secondary treatment failure. Chronic TNF blockade also heightens infection risks, including latent tuberculosis reactivation. Emerging targeted protein degradation (TPD) technologies, such as LYTACs and KineTACs, offer promising alternatives, yet all rely on the host's endogenous degradation machinery and require repeated dosing—making them poorly suited to chronic disease management.
"Existing anti-TNF (search) biologics rely on neutralization rather than degradation, while all current targeted protein degradation tools borrow the host's endogenous protein degradation machinery—an approach that can introduce unpredictable side effects and fundamentally limits durability," said Professor Min Peng, corresponding author and researcher at Tsinghua University's Institute for Immunology. "By recruiting an exogenous cellular platform—CAR-T cells—to perform the degradation, we bypass this limitation entirely. Our vision is a one-time intervention that provides years of sustained benefit for patients with chronic inflammatory disease."
Engineering and Persistence Without Preconditioning
The TNFR1 CAR was constructed by fusing the mouse TNFR1 ectodomain (amino acids 1–212) with CD28 co-stimulatory and CD3ζ signaling domains. To overcome a key translational barrier—conventional CAR-T cells' failure to expand without lymphodepleting preconditioning—the team co-deleted Bcor and Zc3h12a via CRISPR-Cas9. The resulting TNFR1TIF (search) cells expanded robustly and maintained stable levels in peripheral blood for more than one year in fully immunocompetent mice, with no conditioning regimen required.
Their persistence proved strictly TNF (search)-dependent, as expansion was abolished in TNF-knockout animals. A single infusion lowered serum human TNF to near wild-type levels. Twelve-month safety monitoring revealed no disruption of endogenous T cell homeostasis, organ integrity, or antibacterial immunity. A pharmacological safety switch—anti-Thy1.1 depleting antibody—efficiently eliminated TNFR1TIF (search) cells in vivo, providing a controllable fail-safe mechanism for potential clinical translation.
Broad Applicability and Future Directions
This work marks a conceptual shift in the targeting scope of CAR-T cell therapy, extending it from cell-surface antigens to soluble extracellular proteins. The platform is broadly applicable: other disease-relevant cytokines (IL-1β, IL-4, IL-17) and extracellular aggregates, such as amyloid-β in Alzheimer's disease, are natural candidates. The team envisions adapting the safety switch to the clinical setting by substituting FDA-approved surface markers, such as truncated EGFR or CD20, targetable by cetuximab or rituximab, respectively.
The research was conducted at the State Key Laboratory of Molecular Oncology, Institute for Immunology, and School of Basic Medical Sciences, Tsinghua University, Beijing, China, in collaboration with Shanxi Medical University. Support was provided by the National Natural Science Foundation of China (Grant Nos. T2495270 and 82350108), the Tsinghua University DUSHI Program (Grant No. 52302102323), the Tsinghua-Peking Center for Life Sciences, and the SXMU-Tsinghua Collaborative Innovation Center for Frontier Medicine.