Allogeneic Mesenchymal Stromal Cells Increase Type 1 Regulatory T Cells and Decrease Aneurysm Volume in Patients With Small Abdominal Aortic Aneurysms

Abstract

We have previously demonstrated that patients with abdominal aortic aneurysms (AAA) have a defect in IL-10 expression, type 1 regulatory T cell (Tr1) function and a robust Th17 response. In this phase I, double masked, placebo-controlled trial, we assess the efficacy of intravenous delivery of escalating doses of allogeneic mesenchymal stromal cells in modulating immune responses in patients with small AAA. Patients with AAA less than 5.0 cm in diameter were randomized 1:1:1 to receive intravenous administration of placebo (Plasmalyte A), 1 million mesenchymal stem cells (MSCs)/kg, or 3 million MSCs/kg. The primary end point were changes in Tr1 cells at day 14 after treatment as measured by fluorescent activated cell sorting. Secondary end points included changes in aneurysm inflammation at day 14 as measured by positron emission tomography and change in AAA volume at 1 year as measured by a computed tomography scan. Changes in plasma cytokines using enzyme linked immunoassay were measured at days 7, 14, and 28 after treatment. Treatment-related adverse outcomes and adverse cardiac events were recorded. A total of 28 patients (28 male; mean age 66 ± 4 years) with small AAA (mean diameter 3.9 ± 0.6 cm) were randomized to placebo (n = 12), 1 million MSCs/kg (n = 6), or 3 million MSCs/kg (n = 10). There was a significant increase in the percent of Tr1 cells at day 14 compared with placebo in the high dose group (73.2 ± 6.9% vs –5.5 ± 20.1%; P = .02), but not in the low-dose group. There was a decrease in Th17 cells at day 14 compared with placebo in the high and low dose groups (–11.1 ± 4.3% and –13.3 ± 4.6% vs 9.7 ± 5%, respectively; P < .05). Compared with placebo, there was a significant increase in IL-10 in the high- and low-dose groups (28.8 ± 3.2 pg/mL and 42.7 ± 4.5 pg/mL vs 11.9 ± 2.1 pg/mL; P = .034 and .023, respectively) at day 7. There was a decrease in aneurysm volume in the high-dose group compared with placebo at 1 year, but it was not quite significant (–7.3 ± 0.14 mm3vs 12.3 ± 2.6 mm3; P = .055) (Figure). There were no changes in aortic inflammation and no treatment-related adverse events. The ARREST study demonstrates that systemic administration of allogeneic MSCs is safe and may reduce AAA expansion. We plan a multicenter multidosing trial to further assess the potential of MSCs in preventing AAA expansion.