Allogeneic Human Mesenchymal Stem Cell Infusions for Aging Frailty

Abstract

Background: Impaired endogenous stem cell repair capacity is hypothesized to be a biologic basis of frailty. Therapies that restore regenerative capacity may therefore be beneficial. This Phase 1 study evaluated the safety and potential efficacy of intravenous, allogeneic, human mesenchymal stem cell (allo-hMSC)-based therapy in patients with aging frailty.

Methods: In this nonrandomized, dose-escalation study, patients received a single intravenous infusion of allo-hMSCs: 20-million (n = 5), 100-million (n = 5), or 200-million cells (n = 5). The primary endpoint was incidence of any treatment-emergent serious adverse events measured at 1 month postinfusion. The secondary endpoints were functional efficacy domains and inflammatory biomarkers, measured at 3 and 6 months, respectively.

Results: There were no treatment-emergent serious adverse events at 1-month postinfusion or significant donor-specific immune reactions during the first 6 months. There was one death at 258 days postinfusion in the 200-million group. In all treatment groups, 6-minute walk distance increased at 3 months (p = .02) and 6 months (p = .001) and TNF-α levels decreased at 6 months (p < .0001). Overall, the 100-million dose showed the best improvement in all parameters, with the exception of TNF-α, which showed an improvement in both the 100- and 200-million groups (p = .0001 and p = .0001, respectively). The 100-million cell-dose group also showed significant improvements in the physical component of the SF-36 quality of life assessment at all time points relative to baseline.

Conclusions: Allo-hMSCs are safe and immunologically tolerated in aging frailty patients. Improvements in functional and immunologic status suggest that ongoing clinical development of cell-based therapy is warranted for frailty.

Keywords: Cell-based therapy; Inflammation; Physical function; Regenerative medicine.

Figure 1.

Immune monitoring. (A) Effects of mesenchymal stem cells (MSCs) on cPRA. Change in Calculated Panel Reactive Antibody (cPRA) assay from day 1 to 6 months demonstrates that only one subject in the 20-million (M) arm had a moderate donor-specific cPRA reaction and no subjects in the 100M and the 200M group had any reaction. (B) Effects of MSCs on early T cell activation. Change in T cells expression of early activation marker CD69 demonstrates that allo-hMSCs in all treatment arms suppresses early T cell activation. (C) Effects of MSCs of late/chronic T cell activation. Change in T cells expression of late/chronic activation marker CD25 demonstrates that allo-hMSCs in all treatment arms did not induce late/chronic T cell activation and the 20 million dose significantly suppressed activation (*p = .03) at 6 mo as compared to baseline.

Figure 2.

Effects of mesenchymal stem cells (MSCs) on physical markers of frailty. (A) Change in 6-minute walk distance (6MWD). The average 6MWD significantly improved from baseline for subjects in the 20-million (M) (at 6 mo, p = .043) and 100M arms (at 3 mo, p = .033 and at 6 mo, p = .0005) but not the 200M arm. *p Values are for within group versus baseline. (B) Change in forced expiratory volume in 1 s (FEV1). The average FEV1 significantly improved for subjects in the 200-million (M) arm (at 3 mo, p = .02) but not the 20 or 100M arms. *p Values are for within treatment arm versus baseline. (C) SF-36 Physical Component Score Improvement. The average physical component score improved for subjects in the 100-million (M) (at 1 mo, p = .002; at 3 mo, p = .03; and at 6 mo, p = .03) allo-hMSCs cell-dose group at 1, 3, and 6 mo. *p Values are for within treatment arm versus baseline.

Figure 3.

Tumor necrosis factor-α levels decreased with allogeneic mesenchymal stem cell (MSC) treatment. Serum levels significantly decreased over 50% at 6 mo after infusion with allogeneic MSCs in both the 100M and 200M groups (100M and 200M p = .0001). *p Values are for within treatment arm versus baseline.