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 end-stage pulmonary emphysema and to compare with historic lung function data of a…
ID
Source
Brief title
Condition
- Lower respiratory tract disorders (excl obstruction and infection)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
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. Safety will be
evaluated according to WHO criteria and in addition change in outcome of lung
function by the surgery and MSC treatment will be compared with a cohort of
LUMC patients treated by lungvolumereduction surgery in LUMC and of whom
similar lung function data were obtained.
Secondary outcome
Disease specific transpleural air leakage measured in days after the day of
surgery.
The surgeon will insert a chest tube after removal of emphysematous tissue.
Transpleural air leakage can be measured with a flow meter connected to
drainage reservoir. The number of days with air leakage through the tube will
be counted after each LVRS. The difference in days between the first and second
LVRS session is the primary outcome parameter
Ex-vivo analysis of MSC-induced effects:
Immunohistochemical examination of resected tissue of both left (not
MSC-treated) and right (MSC-treated) lung from each patient will be analysed
for inflammatory cell markers and markers of tissue repair and fibrosis.
Inflammatory cell infiltrates will be analyzed using markers for T cells (CD3,
CD4 and CD8), B cells (CD20), macrophages (CD68), neutrophils (elastase),
eosinophils (EG2), and mast cells (AA1; mast cell tryptase). To assess early
fibrotic events, we will determine total collagen deposition and expression of
mooth muscle actin, a smooth muscle cell marker that is also expressed in
myofibroblasts. Ki67 staining will be used as a marker for proliferating cells,
together with VEGF and other markers for tissue repair that will be further
defined based on the findings. Finally, we will assess the local expression of
hCAP18/LL-37, an antimicrobial peptide that has recently been identified as a
chemoattractant for MSC. In this way we will compare MSC-induced effects
within patients and between patients.
inn-vivo analysis of MSC on lung tissue:
Before LVRS and one year after the second LVRS, patients will be assessed for
lung density by chest CT scan according to a published acquisition protocol.
Both chest CT scans are part of the standard chain of procedures associated
with 2-sided LVRS. The difference in 15th percentile point of the histogram of
lung densities between left and right lung measured before and after surgery is
a secondary end point.
Comparison of change in lung function due to treatment by current protocol
compared with historic LVRC treatment from LUMC with MSC infusions.
Background summary
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 in
vitro 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 we 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.
Study 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 end-stage pulmonary emphysema and to compare with historic lung function
data of a similar patient population from LUMC.
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 at, 4 and 3 weeks prior to the lung surgery. The intervention consists of
two doses of BM-MSC infusions of 1-2 x 10/6 MSC/kg body weight in 10 patients
with a one week interval, 4 and 3 weeks prior to the second LVRS respectively.
Intervention
Two intravenous infusions of autologous bone marrow derived mesenchymal
stemcells
Study burden and risks
Two CT scans, one as part of routine screening procedure prior to LVRS, one
additional at the end of the 1 yr follow-up period; LVRS in 2 sessions as part
of standard clinical care; BM aspiration (100 ml) during the first LVRS under
general anesthesia; intravenous administration of two doses of BM-MSC prior to
the second LVRS procedure; 10 visits to the hospital (8 routine), 2 extra for
BM-MSC infusions.
Initial phase I studies involving autologous bone marrow-derived MSC showed
that MSC could be successfully collected, culture-expanded ex-vivo for 4-7
weeks and administered to patients with hematological malignancies in complete
remission. The transfusions contained up to 50 x 106 BM-MSC and were well
tolerated without adverse reactions. In a subsequent phase I-II clinical trial
in patients with breast cancer, autologous and expanded BM-MSC were co-infused
with autologous peripheral blood progenitor cells. No toxicities were observed
related to the transfusion of BM-MSC and hematopoietic reconstitution was
rapid, suggesting some efficacy of BM-MSC transfusion on hematopoietic
reconstitution.
In another multi-center phase I-II study, allogeneic donor BM-MSC were
co-infused in patients with hematological malignancies undergoing matched
sibling stem cell transplantation. Preliminary data suggests that there was no
immediate toxicity following transfusion of BM-MSC and that there was a more
rapid engraftment and a lower incidence of acute Graft versus Host Disease
(GvHD) in comparison with historical controls.
The ability of BM-MSC to suppress immune responses following autologous bone
marrow transplantation was initially shown in a case study of sever grade IV
GvHD. Le Blanc et al. has reported that repeated administration of purified
haploidentical human BM-MSC following allogeneic stem cell transplantation
completely reversed GvHD. The results of this case study have recently been
confirmed in a multicenter phase II trial for the treatment of severe acute
GvHD, showing complete response in 30 of 55 patients treated with BM-MSC
Albinusdreef 2
2333 ZA
NL
Albinusdreef 2
2333 ZA
NL
Listed location countries
Age
Inclusion criteria
For entry in the study, the following criteria must be met:
a) Men and women over 50 years of age and must have stopped smoking for more than 6 months.
b) Subject is willing to participate in the study and has signed the informed consent.
c) Subject must have emphysema in both lungs demonstrated on a chest CT scan.
d) Subjects must have less than 15% difference in lung density between left and right lung as assessed by PulmCMS software in chest CT scan DICOM files.
e) Subject must have FEV1 below 40% pred (post-bronchodilator).
f) Subject must have a Kco gastransfer factor < 40% pred.
g) Subject must have flat diaphragm as demonstrated on chest film.
h) Patients must be able to adhere to the study visit schedule and protocol requirements.
i) Patient must be willing to participate in a pre-operative rehabilitation protocol.
j) Patients must be able to give informed consent and the consent must be obtained prior to any study procedure.
Exclusion criteria
a) Patients with clinical and radiological evidence of bronchiectasis.
b) Patients suffering from renal- or hepatic failure.
c) A psychiatric, addictive, or any disorder that compromises ability to give truly informed consent for participation in this study.
d) Use of any investigational drug within 1 month prior to screening
e) Patients with pulmonary hypertension, with mean PAP above 30 mmHg assessed by ultrasound of the chest or by transoesophageal ultrasound.
f) Documented HIV infection.
g) Active hepatitis B, hepatitis C or TB.
h) Subjects who currently have or who have had an opportunistic infection (e.g., herpes zoster [shingles], cytomegalovirus, Pneumocystis carinii, aspergillosis, histoplasmosis, or mycobacteria other than TB) within 6 months prior to screening.
i) Current signs or symptoms of severe, progressive or uncontrolled renal, hepatic, hematologic, gastrointestinal, endocrine, cardiac, neurologic, or cerebral disease (including demyelinating diseases such as multiple sclerosis).
j) Malignancy within the past 5 years (except for squamous or basal cell carcinoma of the skin that has been treated with no evidence of recurrence).
k) History of lymphoproliferative disease including lymphoma, or signs and symptoms suggestive of possible lymphoproliferative disease, such as lymphadenopathy of unusual size or location (such as nodes in the posterior triangle of the neck, infra-clavicular, epitrochlear, or periaortic areas), or splenomegaly.
l) Known recent substance abuse (drug or alcohol).
m) Poor tolerability of venapuncture or lack of adequate venous access for required blood sampling during the study period.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2009-013551-29-NL |
| CCMO | NL28562.000.09 |