Allogeneic Mesenchymal Stem Cells Ameliorate Aging Frailty: A Phase II Randomized, Double-Blind, Placebo-Controlled Clinical Trial

Abstract

Background: Aging frailty, characterized by decreased physical and immunological functioning, is associated with stem cell depletion. Human allogeneic mesenchymal stem cells (allo-hMSCs) exert immunomodulatory effects and promote tissue repair.

Methods: This is a randomized, double-blinded, dose-finding study of intravenous allo-hMSCs (100 or 200-million [M]) vs placebo delivered to patients (n = 30, mean age 75.5 ± 7.3) with frailty. The primary endpoint was incidence of treatment-emergent serious adverse events (TE-SAEs) at 1-month postinfusion. Secondary endpoints included physical performance, patient-reported outcomes, and immune markers of frailty measured at 6 months postinfusion.

Results: No therapy-related TE-SAEs occurred at 1 month. Physical performance improved preferentially in the 100M-group; immunologic improvement occurred in both the 100M- and 200M-groups. The 6-minute walk test, short physical performance exam, and forced expiratory volume in 1 second improved in the 100M-group (p = .01), not in the 200M- or placebo groups. The female sexual quality of life questionnaire improved in the 100M-group (p = .03). Serum TNF-α levels decreased in the 100M-group (p = .03). B cell intracellular TNF-α improved in both the 100M- (p < .0001) and 200M-groups (p = .002) as well as between groups compared to placebo (p = .003 and p = .039, respectively). Early and late activated T-cells were also reduced by MSC therapy.

Conclusion: Intravenous allo-hMSCs were safe in individuals with aging frailty. Treated groups had remarkable improvements in physical performance measures and inflammatory biomarkers, both of which characterize the frailty syndrome. Given the excellent safety and efficacy profiles demonstrated in this study, larger clinical trials are warranted to establish the efficacy of hMSCs in this multisystem disorder.

Clinical trial registration: www.clinicaltrials.gov: CRATUS (#NCT02065245).

Keywords: Immunomodulation; Regenerative medicine; Tumor necrosis factor-α.

Figure 1.

Study flow chart. Patient screening, follow-up, and randomization in a 1:1:1 fashion to either the 100M-group, 200M-group, or placebo. M = Million.

Figure 2.

Physical markers of frailty. (A) Six-minute walk test (6MWT) increased in mean meters walked in the 100M-group from baseline to 6 months (p = .011) but not the 200M-group (p = .263) or placebo (p = .112). (B) Short physical performance battery (SPPB) was significant for an overall improvement in the median total score in the 100M-group from baseline to 6 months (p = .031) but not in the 200M-group (p = .812) or placebo (p = .875). (C) Community Healthy Activities Model Program for Seniors (CHAMPS) questionnaire was significant for a reduced median total caloric expenditure per week at moderate intensity from baseline to 6 months in the 200M-group (p = .008) and placebo (p = .039), but not in the 100M-group (p = .641). (D) Forced expiratory volume after 1 second (FEV1) improved in mean liters from baseline to 6 months in the 100M-group (p = .025) without changes noted in the 200M-group (p = .259) or placebo (p = .883). * indicates p ≤ .05.

Figure 3.

Immune biomarkers in frailty. All time points are from baseline to 6 months except for TNF-α which begins on Day 1 (infusion) through 6 months. (A) Early T-cell activation (CD3, CD69) were reduced as a percent change from baseline to 6 months in the 200M-group (p = .004), but not the 100M-group (p = .269) or placebo (p = .0797). (B) Late T-cell activation (CD3, CD25) was reduced as a percent change from baseline to 6 months in the 100M and 200M-groups (p = .007 and p = .048 respectively), but not in the placebo (p = .119). (C) % CD8 T-cells decreased from baseline to 6 months in the 200M-group (p = .022) and no changes were noted in the 100M-group (p = .978) or placebo (p = .0797). (D) CD4/CD8 ratio increased from baseline to 6 months in the 200M-group (p = .014) and no changes were found in the 100M-group (p = .609) or placebo (p = .104). (E) Serum TNF-α decreased in pg/mL from baseline to 6 months in the 100M-group (p = .031) without a change in the 200M-group (p = .129) or placebo (p = .094). (F) %B cells expressing intracellular TNF-α decreased from baseline to 6 months in the 100M (p < .0001) and 200M-groups (p = .002) without a significant change in placebo (p = .869). * indicates p ≤ .05.

Figure 4.

Sexual quality of life-female (SQOL-F) questionnaire. There was a mean increase in the 100M-group (p = .0348) from baseline to 6 months as compared to the 200M-group (p = .882) and placebo (p = .941). * indicates p ≤ .05.