Mesenchymal stem cell therapy improves pulmonary function and exercise tolerance in patients with chronic obstructive pulmonary disease (copd) and high baseline inflammation

Abstract

Background & Aim Background Mesenchymal stem cells (MSC) respond to activation by pro-inflammatory cytokines by secreting anti-inflammatory mediators which downregulate multiple immune pathways. Aim To evaluate whether inflammation at baseline, as measured by C-reactive protein (CRP), predicts clinical responses in COPD patients to the allogeneic mesenchymal stem cell product candidate remestemcel-L. Methods, Results & Conclusion Methods 62 patients with moderate to severe COPD were randomized in a double-blind manner to 4 monthly intravenous infusions of either allogeneic MSCs (remestemcel-L, 100 × 106 cells/infusion) or vehicle control. Subjects were followed for 2 years after the first infusion for safety and efficacy endpoints, including pulmonary function testing, 6-minute walk distance (6MWD) and assessments of systemic inflammation. While full study results were previously reported (DOI: 10.1378/chest.12-2094), here we report post-hoc analyses comparing outcomes of remestemcel-L and controls in patients with CRP levels < 2 and in those with CRP levels ≥2, ≥3, and ≥4 mg/mL. Results At day 120 (first visit after completing infusions), remestemcel-L treated patients with baseline CRP ≥2, ≥3 or ≥4 mg/mL had significantly greater improvement in FEV1, FVC or 6MWT than controls (Table 1). In contrast, there was no improvement with MSC treatment in patients with CRP<4. Degree of improvement with MSC increased with progressive increases in baseline CRP level. In those with CRP≥4, significant reductions in FEV1 and increases in 6MWT were observed in MSC compared to controls at each study visit (overall) and at the Day 120 follow-up visit following the monthly infusions (Figure 1). Conclusion Stratification of COPD patients by degree of elevated baseline CRP level identifies patients most likely to respond to MSC treatment with improvement in pulmonary and overall physical function. The correlation between highest CRP levels and greatest degree of response suggests that the inflammatory component of the lung disease may trigger and be amenable to the immunomodulatory effects of MSC treatment. Mesenchymal stem cells (MSC) respond to activation by pro-inflammatory cytokines by secreting anti-inflammatory mediators which downregulate multiple immune pathways. To evaluate whether inflammation at baseline, as measured by C-reactive protein (CRP), predicts clinical responses in COPD patients to the allogeneic mesenchymal stem cell product candidate remestemcel-L. 62 patients with moderate to severe COPD were randomized in a double-blind manner to 4 monthly intravenous infusions of either allogeneic MSCs (remestemcel-L, 100 × 106 cells/infusion) or vehicle control. Subjects were followed for 2 years after the first infusion for safety and efficacy endpoints, including pulmonary function testing, 6-minute walk distance (6MWD) and assessments of systemic inflammation. While full study results were previously reported (DOI: 10.1378/chest.12-2094), here we report post-hoc analyses comparing outcomes of remestemcel-L and controls in patients with CRP levels < 2 and in those with CRP levels ≥2, ≥3, and ≥4 mg/mL.