Abstract
Abstract Biologic therapies have transformed the lives of people with moderate-to-severe psoriasis, however, management of the disease remains challenging for those who have failed all available treatments. Mesenchymal stromal cells (MSCs), owing to their hypoimmunogenic and immunomodulatory properties, have shown promise in treating various immune-mediated inflammatory diseases. We investigated whether allogeneic umbilical cord-derived MSCs (UC-MSCs) could be used to manage severe, multiple biologic-refractory psoriasis. On compassionate grounds, we treated three women (Patients 1–3), aged 44, 46 and 47 years, respectively, with long-standing plaque psoriasis; on treatment, baseline psoriasis area and severity index (PASI) were 37.6, 13.8 and 22.8; and DLQI 27, 15 and 20, respectively. All patients had failed at least five biologics across all four classes. Allogeneic UC-MSCs were administered intravenously at a dose of 1.5–3 × 106cells/kg on Days 0 and 7, as adjuvant therapy alongside etanercept biosimilar in Patient 1 and monotherapy in Patients 2 and 3. Peripheral blood mononuclear cells (PBMCs) were immunophenotyped using multi-parameter flow cytometry. UC-MSCs were well-tolerated and provided variable, direct clinical benefit in all patients: Patient 2, the best responder, achieved PASI87 at Week (W)4 whereas Patient 1 experienced the most durable, albeit moderate, response with PASI39 at W2, lasting >20 weeks. DLQI also improved post-UC-MSCs, up to 17-point reduction at W2 in Patient 1. Upon psoriasis flare post-UC-MSCs, Patient 1 switched to a new biologic, bimekizumab at W24 whereas Patients 2 and 3 were re-initiated on previously failed biologics – guselkumab and bimekizumab, respectively, at W9. Patients 2 and 3 demonstrated a greatly improved response to previously failed biologics, achieving PASI94 (16.9 to 1) and PASI96 (29.1 to 1.2) from the time of biologic re-initiation respectively, sustained for >12 months. Flow cytometry of PBMCs in individual patients showed overall increased frequencies of CD4+CLA+CD103- skin-homing and CD4+CLA+CD103+ skin-recirculating memory T cells, associated with reductions in PASI. Similar trends occurred for CD8+ counterparts and following re-initiation of previously failed biologics. There was phenotypic switch of peripheral blood monocytes from CD14+CD16+ intermediate to CD14lowCD16+ non-classical, suppressive phenotype post-UC-MSCs. Furthermore, an exponential rise in frequency of CD25highCD127lowFOXP3+ regulatory T cells (Tregs) was observed in the most durable responder, i.e. Patient 1. Together, these data highlight the immunomodulatory capacity of UC-MSC therapy in severe multiple biologic-refractory psoriasis, possibly by increasing Tregs frequency, phenotypic switching of monocytes and reducing the migratory capacity of pathogenic T cells to involved skin. Immune changes occurred in parallel to clinical efficacy. It appears that UC-MSCs may reset the immune profile thereby facilitating restoration of response to previously failed biologics. The use of UC-MSCs for severe psoriasis warrants a full clinical trial.
Published Version
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