Safety and Feasibility Study of Administration of Mesenchymal Stemcells for Treatment of Emphysema
Condition: Emphysema
MeSH terms: Pulmonary Emphysema; Emphysema
Study type: Interventional
Phase: Phase 1

Summary: 
      The purpose of this study is to show safety and feasibility to administer patients own
      mesenchymal stem cells to show signs of repair of emphysematous lung tissue
    

Detailed description: 
      Study Rationale Emphysema is one of the two main components of chronic obstructive pulmonary
      disease (COPD) and contributes over many years to airway obstruction by the loss of elastic
      recoil around the smallest airways. Emphysema is induced by cigarette smoking and it is
      widely accepted that the disease is caused by excessive proteolytic activity by proteases and
      a chronic inflammatory process, characterized by a cellular influx consisting of macrophages,
      neutrophils and T cells. This inflammatory response is steroid resistant and leads to slow
      but persistent alveolar destruction, resulting in enlarged lungs with bullous parts in both
      lungs. In addition to a central role of innate immunity, recent studies suggest that also
      (auto)antigen specific immunity may play a role in the pathogenesis of COPD.

      Currently, the only treatment available for severe emphysema is lung volume reduction surgery
      (LVRS) to remove the most destroyed parts of the lungs. The surgery is generally performed in
      two separate sessions with a 10-12 weeks interval, with each lung as a separate surgical
      target. This surgical treatment allows improved ventilation in the remaining less affected
      areas of the lungs as demonstrated by post-surgical clinical improvement of lung function and
      increased survival in a subgroup of patients. Delayed wound healing after LVRS is an
      important clinical problem. It may lead to prolonged hospital stay due to air leakage from
      the lungs into the thoracic cavity. Lung emphysema patients are at high risk for prolonged
      air leakage after this surgery, which is most likely explained by the inflammatory process
      related to the disease.

      Mesenchymal stromal cells (MSC) are multipotent cells that can differentiate into several
      cell types, including fibroblasts, osteoblasts, adipocytes and chondrocyte progenitors. In
      recent years it has become evident that bone-marrow derived MSC (BM-MSC) have potent
      immunomodulatory effects on T and B cells and in animal models of chronic inflammation in
      vivo. In addition, it has been shown that MSC express or release a variety of soluble factors
      implicated in anti-apoptotic signaling and cell growth. Importantly, encouraging results have
      recently been obtained with the treatment of severe steroid resistant Graft versus Host
      Disease (GvHD) with donor (allogeneic) BM-MSC. Furthermore, in our institute autologous
      BM-MSC are currently under investigation for treatment of tissue injury due to autoimmune
      disease (Crohn's Disease) and allogeneic immune responses (renal transplant recipients with
      biopsy proven subclinical rejection). The combination of the immunosuppressive,
      growth-potentiating and anti-apoptotic properties of BM-MSC may lead to accelerated wound
      healing after LVRS and might induce lung repair. In the present phase I study the
      investigators will assess the safety and feasibility of intravenous (i.v.) administration of
      BM-MSC prior to LVRS in a small group of severe pulmonary emphysema patients. Results of this
      safety and feasibility study may lead to future studies on the use of BM-MSC for
      immunomodulation and induction of repair in patients with pulmonary emphysema and milder
      stages of COPD.

      Objective To test the safety and feasibility of intravenous administration of autologous
      BM-MSC after one-sided LVRS and prior to a second LVRS procedure for patients with severe
      pulmonary emphysema.

      Study design Open label, non-randomized, non-blinded, prospective clinical trial. Patients
      are operated in two sessions; initially on one lung without pre-surgical infusion of BM-MSC,
      followed by a second surgical procedure on the contralateral lung which is preceded by two
      i.v. infusions of BM-MSC one week apart, 4 and 3 weeks prior to the lung surgery.

      Study population Patients of at least 40 years of age with end-stage emphysema who are
      eligible for lung volume reduction surgery.

      Intervention The intervention consists of two doses of BM-MSC infusions in 10 patients with a
      one week interval, 4 and 3 weeks prior to the second LVRS respectively.

      Study endpoints

      Primary endpoint:

      1. Safety and feasibility of intravenous infusion of two doses of BM-MSC with 1 wk interval
      after the first LVRS and prior to a second LVRS. Toxicity criteria will be evaluated by grade
      according to WHO.

      Secondary endpoint:

        1. Difference in days between post-surgical transpleural air leak of the lung in each
           patient after the first (no infusion of BM-MSC) and second surgical (3 weeks after the
           last i.v. infusion of BM-MSC) intervention.

        2. Histological responses in resected lung tissue (measured by immunohistochemistry of
           markers of inflammation, fibrosis and repair).
    

Intervention name(s): autologous bone marrow derived mesenchymal stromal cells
Intervention type(s): Biological
Intervention description(s): Intravenous administration of autologous bone marrow-derived mesenchymal stromal cells.
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: emphysema; lung volume reduction surgery; mesenchymal stromal cells