uPAR CAR-T therapy reduced thrombus weight by 41% (p=0.004) and collagen content by 55% (p=0.002) compared with untransduced controls in a murine model of CTEPH.
Does uPAR-CAR T cell therapy reduce thrombus burden and improve cardiopulmonary function in a murine model of CTEPH?
Targeting uPAR+ macrophages and fibroblasts with CAR-T therapy reduces thrombus burden and improves right ventricular function in a preclinical model of CTEPH.
Effect estimate: 41% reduction
p-value: p=0.004
Abstract Purpose CTEPH is sustained by nonresolving thrombi enriched with inflammatory macrophages and fibrotic stromal populations. We hypothesized that targeting these cell subsets could remodel the thrombus niche and improve cardiopulmonary function. Methods scRNA-seq of human PTE clots and murine IVC wall and thrombi identified uPAR as a shared marker of pathogenic macrophages and fibroblasts. Murine T cells engineered with a uPAR-CAR were infused into IVC-ligated mice (n = 9/group). Outcomes included scRNA-seq validation, histology, cytokine assays, echocardiography, and flow analysis. Results scRNA-seq showed that uPAR+ macrophages expressed pro-inflammatory chemokines (Ccl6, Ccl8, Ccl12), while uPAR+ fibroblasts and vascular cells upregulated fibrogenic genes (Fn1, Timp1/2, Col15a1). In vivo, CAR-T treatment reduced thrombus weight by 41% (p = 0.004) and collagen content by 55% (p = 0.002) compared with untransduced controls. α-SMA+ myofibroblasts decreased ∼4-fold (p=0.001). Serum TNF-α, IL-1β, IL-6, and CCL2 were significantly reduced (p0.05). Echocardiography revealed lower RV systolic pressure (-18%, p=0.03) and improved RV function (p=0.02). Respiratory testing under hypoxia/hypercapnia showed robust gains: minute ventilation +35% (p=0.0006), tidal volume +27% (p=0.0001), and peak inspiratory/expiratory flow +30% (p=0.0001). In human PTE clots, high uPAR+ burden correlated with residual pulmonary pressures post-surgery (p=0.01). Conclusion uPAR+ macrophages and stromal subsets drive persistent immune-fibrotic pathology in CTEPH. uPAR CAR-T therapy effectively depletes these populations, reduces fibrosis, lowers inflammation, and restores vascular and cardiopulmonary function. These results highlight a new therapeutic strategy for immune-fibrotic remodeling in pulmonary vascular disease. This abstract is funded by: None
Mohammed et al. (2026) studied Chronic Thromboembolic Pulmonary Hypertension (CTEPH) (n=18). uPAR-CAR T cells vs. untransduced controls was evaluated on thrombus weight (41% reduction, p=0.004). uPAR CAR-T therapy reduced thrombus weight by 41% (p=0.004) and collagen content by 55% (p=0.002) compared with untransduced controls in a murine model of CTEPH.
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