In rheumatoid arthritis, rogue structural cells called fibroblasts turn the joint into a hostile environment that recruits inflammatory cells and remembers past inflammation, causing the disease to keep returning to the same joints. Current treatments manage symptoms but do not target these fibroblasts, so many patients relapse when therapy stops. The researchers have engineered immune cells—CAR-T cells—that recognise a protein called FAPa, found only on these harmful fibroblasts. In mouse models, the CAR-T cells travel to inflamed joints, kill the FAPa-expressing fibroblasts, and reduce both inflammation and joint damage. If this approach works in humans, it could fundamentally change arthritis treatment. Instead of suppressing symptoms indefinitely, a single course of CAR-T therapy might reset the joint’s tissue environment to a healthy state, preventing recurrence even after treatment ends. The team will now test whether this depletion erases the tissue’s inflammatory “memory,” optimise dosing and timing, and assess safety in mice. They will also trial a new method of generating CAR-T cells that avoids long-term persistence, which has caused side effects in other diseases. This is still preclinical work, but it addresses a root cause of arthritis relapse that no existing drug tackles.
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In rheumatoid arthritis (RA), the body’s own immune system mistakenly attacks the joint tissues, resulting in inflammation (a process causing redness, swelling, heat, and pain) that drives progressive joint damage. Fibroblasts are structural cells that form the lining of healthy joint tissue, but become abnormally activated during arthritis, directly contributing to both inflammation and damage. Our research has shown that these fibroblasts contribute to RA by curating a ‘microenvironment’ within the joint that is favourable to the recruitment and survival of inflammatory cells. Fibroblasts are also known to develop a ‘memory’ of their experience of inflammation, and this is thought to be one reason why arthritis has a strong tendency to recur in the same joints over time. Fibroblasts have yet to be targeted directly by any currently available treatments. This may explain why, even when arthritis is well-controlled, many individuals quickly experience a relapse of their arthritis following cessation of treatment. We propose, to improve the long-term outcomes for people affected by arthritis, that we must reverse this pathogenic ‘microenvironment’ within the joint. Therefore, we aim to test the hypothesis that targeted depletion of pathogenic fibroblasts from the inflamed joint induces a therapeutic RESET of the joint microenvironment, restoring the joint tissue to a healthy state. To achieve this goal, we have engineered a certain type of cell, called T cells, to express a receptor (chimeric antigen receptor, CAR-T cell) that recognises a protein called fibroblast activation protein-a (FAPa). This protein is expressed by activated fibroblasts in the joint during inflammation – our previous work has demonstrated that these FAPa-expressing fibroblasts drive joint inflammation and damage. Our engineered CAR-T cells can recognise and kill FAPa‑expressing fibroblasts. In mouse models of arthritis, we have shown that these CAR T cells, when injected into the bloodstream, migrate to inflamed joints and kill FAPa-expressing fibroblasts, leading to reduced severity of joint inflammation and damage. In the next critical stage of our research, we aim to further establish the benefit of this potential treatment, including whether it may prevent recurrence of arthritis, by testing whether targeted depletion of FAPa-expressing fibroblasts using CAR-T therapy induces a RESET of the tissue microenvironment to a disease-free state. To achieve this aim, we will conduct experiments in mouse models of inflammatory arthritis to test whether depletion of FAPa-expressing fibroblasts by CAR-T cells is able to suppress the development of inflamed tissue “memory” and perform a comprehensive analysis of the cells in the joint tissue to assess whether the pathogenic microenvironment has been reversed. Furthermore, we will prepare for future first-in-human studies by optimising the delivery, dosing and timing of CAR-T therapy and establishing its safety and toxicity profiles using mouse models of inflammatory arthritis. Additionally, the feasibility of a novel method of CAR-T cell generation will be tested, which may help overcome post-treatment CAR-T cell persistence which has been observed in other diseases, providing a potential alternative approach for depletion of FAPa-expressing fibroblasts.
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