A phase I study for intravenous autologous mesenchymal stromal cell administration to patients with severe emphysema

Abstract

Background: Mesenchymal stromal cells (MSCs) may reduce inflammation and promote tissue repair in pulmonary emphysema.

Aim: To study the safety and feasibility of bone marrow-derived autologous (BM-) MSC intravenous administration to patients with severe emphysema.

Design: A phase I, prospective open-label study registered at ClinicalTrials.gov as NCT01306513 Eligible patients had lung volume reduction surgery (LVRS) on two separate occasions. During the first LVRS bone marrow was collected, from which MSCs were isolated and expanded ex vivo After 8 weeks, patients received two autologous MSC infusions 1 week apart, followed by the second LVRS procedure at 3 weeks after the second BM-MSC infusion.

Methods: Up to 3 weeks after the last MSC infusion adverse events were recorded. Using immunohistochemistry and qPCR for analysis of cell and proliferation markers, emphysematous lung tissue obtained during the first surgery was compared with lung tissue obtained after the second surgical session to assess BM-MSC effects.

Results: From 10 included patients three were excluded: two did not receive MSCs due to insufficient MSC culture expansion, and one had no second surgery. No adverse events related to MSC infusions occurred and lung tissue showed no fibrotic responses. After LVRS and MSC infusions alveolar septa showed a 3-fold increased expression of the endothelial marker CD31 (P = 0.016).

Conclusions: Autologous MSC treatment in severe emphysema is feasible and safe. The increase in CD31 expression after LVRS and MSC treatment suggests responsiveness of microvascular endothelial cells in the most severely affected parts of the lung.

Figure 1.

Schematic overview of the study design. Eligible patients had LVRS on two separate occasions. During the first LVRS bone marrow (BM) was collected, from which MSCs were isolated and expanded ex vivo. After clinical recovery, patients received two autologous MSC infusions, followed by the second LVRS procedure. This study protocol is based on previous clinical trials. The expansion of MSCs is described in the supplementary methods.

Figure 2.

FEV₁ and weight measurements at baseline and follow-up. FEV₁ (left) and weight (right) were measured in patients with severe emphysema at baseline prior to the first LVRS procedure (pre), and at 1-year follow-up (post). Individual data points represent individual patients; means are shown as horizontal bars. *P  <  0.05.

Figure 3.

CD31 and SP-C expression analysis in lung tissue before and after MSC infusion. Immunohistochemistry and mRNA expression performed on lung tissue obtained during first LVRS (pre) and a second LVRS procedure that was preceded by two MSC infusions (post). Quantification of CD31 IHC staining with (a) CD31 density, normalized by length of alveolar septa; and (b) CD31 area fraction, normalized by area of alveolar septa. (c) Quantification of IHC staining of SP-C (alveolar type II cell marker) normalized by length of alveolar septa. (d) mRNA expression of SP-C. Data in graph represent mean and individual data points. Paired data n  =  7 for IHC and n  =  6 for mRNA, * P  <  0.05.

Figure 4.

IHC analysis of T cell markers pre- and post- MSC infusion. The number of CD3⁺, CD4⁺and CD8⁺T cells was assessed in surgical specimen obtained before and after MSC infusion. Quantification of (a) CD3, (b) CD4 and (c) CD8, expressed per length of alveolar septa. Data in graph represent mean (horizontal bar) and individual data points. Paired data n  =  7, *P  <  0.05.