Engineered CAR T cells designed to capture and degrade tumor necrosis factor (TNF) produced long-lasting disease control in a mouse model of rheumatoid arthritis, according to a study.
The therapeutic modality is an engineered cellular therapy: CD8-positive T cells modified with a TNFR1-based chimeric antigen receptor and additional CRISPR edits intended to promote long-term persistence. Unlike conventional CAR T therapies, which usually target cell-surface antigens on cancer cells or immune cells, this approach is designed to target a soluble extracellular protein.
The team, led by Min Peng at Tsinghua University, China, engineered CAR T cells carrying the extracellular domain of tumor necrosis factor receptor 1, enabling them to bind soluble TNF. The cells then internalized and degraded TNF through receptor-mediated endocytosis, positioning the platform as a form of cellular targeted protein degradation.
In human TNF-transgenic mice, a single infusion of the optimized cells, called TNFR1TIF cells, reduced serum human TNF to near wild-type levels and prevented or treated rheumatoid arthritis-like disease. In side-by-side experiments, the single infusion produced disease control comparable to repeated high-dose adalimumab, an anti-TNF antibody sold as Humira.
The approach is intended to address a central limitation of existing anti-TNF biologics: the need for repeated dosing over long periods. Long-term biologic use can also be limited by anti-drug antibody formation, which may reduce therapeutic response. By contrast, the engineered cells are designed to persist and repeatedly remove TNF without repeat administration.
To overcome poor CAR T expansion in immunocompetent mice, the researchers used CRISPR-Cas9 to delete two genes, Bcor and Zc3h12a. The resulting TNFR1TIF cells expanded without lymphodepleting preconditioning and persisted in peripheral blood for up to one year in mice. Their expansion was TNF-dependent, disappearing in TNF-knockout animals.
Safety experiments suggested that the cells did not obviously disrupt endogenous T cell homeostasis, body weight, or organ structure over 12 months in mice. The researchers also challenged treated mice with Listeria monocytogenes, a bacterial infection that depends on TNF signaling for immune control, and reported no significant impairment of antibacterial defense. A proof-of-concept safety switch using an anti-Thy1.1 antibody depleted the engineered cells in vivo.
However, the hTNF-transgenic mouse model is a strongly TNF-driven system and does not fully capture the heterogeneity of human rheumatoid arthritis, which can involve multiple cytokines, autoantibodies, and variable TNF dependence. Translation would also require humanized CAR designs, clinically appropriate safety switches, and careful assessment of long-term risks associated with persistent, gene-edited cellular therapies.
The authors suggest that the concept could be adapted beyond TNF to other soluble inflammatory mediators, including IL-1β, IL-4, and IL-17, or even extracellular protein aggregates.
Newsletters
Receive the latest pharmaceutical news, personalities, education, and career development – weekly to your inbox.
