Effect of mesenchymal stromal cell infusions on lung function in COPD patients with high CRP levels

Abstract

Background: We previously reported a Phase 1/2 randomized placebo-controlled trial of systemic administration of bone marrow-derived allogeneic MSCs (remestemcel-L) in COPD. While safety profile was good, no functional efficacy was observed. However, in view of growing recognition of effects of inflammatory environments on MSC actions we conducted a post-hoc analysis with stratification by baseline levels of a circulating inflammatory marker, C-reactive protein (CRP) to determine the effects of MSC administration in COPD patients with varying circulating CRP levels.

Methods: Time course of lung function, exercise performance, patient reported responses, and exacerbation frequency following four monthly infusions of remestemcel-L vs. placebo were re-assessed in subgroups based on baseline circulating CRP levels.

Results: In COPD patients with baseline CRP ≥ 4 mg/L, compared to COPD patients receiving placebo (N = 17), those treated with remestemcel-L (N = 12), demonstrated significant improvements from baseline in forced expiratory volume in one second, forced vital capacity, and six minute walk distance at 120 days with treatment differences evident as early as 10 days after the first infusion. Significant although smaller benefits were also detected in those with CRP levels ≥ 2 or ≥ 3 mg/L. These improvements persisted variably over the 2-year observational period. No significant benefits were observed in patient reported responses or number of COPD exacerbations between treatment groups.

Conclusion: In an inflammatory environment, defined by elevated circulating CRP, remestemcel-L administration yielded at least transient meaningful pulmonary and functional improvements. These findings warrant further investigation of potential MSC-based therapies in COPD and other inflammatory pulmonary diseases.

Trial registration: Clinicaltrials.gov NCT00683722.

Keywords: C-reactive protein; Chronic obstructive pulmonary disease; Inflammation; Mesenchymal stromal cells; Pulmonary function.

Conflict of interest statement

DJW receives research support from the NIH, Department of Defense, Cystic Fibrosis Foundation, and the University of Vermont. RC is a member of the speaker’s bureau for Glaxo Smith Kline, is a consultant for Genentech, Regeneron and Boehringer Ingelheim and is an advisory board member for Astra Zeneca. His laboratory receives research support from Regeneron, Genentech, Boehringer Ingelheim and Glaxo Smith Kline. KS is a former employee of Mesoblast Inc. and JH is a current employee of Mesoblast Inc. DPT is an advisory board member and speaker for AstraZeneca and Mylan/Theravance. DJW, RC, and DPT had previous research support from Osiris Therapeutics, Inc.

Figures

Fig. 1

Changes from baseline in pulmonary function and functional performance from baseline in subjects with baseline CRP > 4 mg/L. Overall treatment effect across all visits were assessed by mixed model with repeated measures (MMRM). Simple differences of treatment by visit are assessed by least squares means using MMRM. Values at each timepoint are means + SEM. *Signifies P values < 0.05. a FEV1 (forced expiratory volume:) P = 0.003 overall by MMRM across all visits and P = 0.015 at day 120. b FVC (forced vital capacity): P = 0.19 overall by MMRM across all visits and P = 0.005 at day 120. c 6MWD (six-minute walk distance): P = 0. 0006 overall by MMRM across all visits and P = 0.004 at day 120

Fig. 2

Changes from baseline in pulmonary function and functional performance from baseline in subjects with baseline CRP 4 mg/L. Overall treatment effect across all visits were assessed by mixed model with repeated measures (MMRM). Simple differences of treatment by visit are assessed by least squares means using MMRM. Values at each timepoint are means + SEM. *Signifies P values < 0.05. a FEV1 (forced expiratory volume:) P = ns overall by MMRM across all visits. b FVC (forced vital capacity): P = ns overall by MMRM across all visits. c 6MWD (six-minute walk distance): P = ns overall by MMRM across all visits and P < 0.05 at day 10 and day 90

Fig. 3

Percent change from baseline in C-reactive protein (CRP) in subjects with baseline CRP ≥ 4 mg/L (panel a) and < 4 mg/L (panel b). Overall treatment effect across all visits using mixed model with repeated measures (MMRM). There were no significant differences between treatment groups overall or at any individual timepoint except as noted. Values are means + SEM. *Signifies P value < 0.05