Emphysema Clinical Trial
Official title:
Effect of Autologous Bone Marrow Derived Mesenchymal Stromal Cells Prior to Lung Volume Reduction Surgery for Severe Pulmonary Emphysema- a Phase I Safety and Feasibility Study
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
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).
;
Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
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