Transcript Poster.Beaune.MSC.2013

INFUSION OF THIRD-PARTY MESENCHYMAL STEM CELLS (MSC)
AFTER KIDNEY AND LIVER TRANSPLANTATION:
A PHASE I-II, OPEN-LABEL, CLINICAL STUDY (EudraCT 2011-001822-81 & NCT01429038)
O. Detry 1, MH Delbouille 1, C Lechanteur 2, J Somja 3, A Deroover 1, L Weekers 4, JP Squifflet 1,
P Honoré 1, P Delvenne 3, M Meurisse 1, E Baudoux 2, Y Beguin 2
1 Dpt
of Abdominal Surgery and Transplantation; 2 Dpt of Hematology; 3 Dpt of Pathology, 4 Dpt of Nephrology
CHU Liège, Sart Tilman B35, University of Liège, Liège, Wallonia, Belgium
Background
Organ transplantation is the only definite treatment of
many critical diseases of the liver, kidney, heart, pancreas
and lung. Although it is the primary therapeutic option at
present, transplanted patients have to deal with the
numerous side effects of life-long dependence on
immunosuppressive drugs, whereas at the same time
these drugs fail to prevent chronic rejection in many
cases. The risk of developing cancer and opportunistic
infections is also markedly increased in solid organ
transplant
recipients
receiving
long-term
immunosuppressive therapy. Cancer and opportunistic
infections cannot be fully avoided, since they result from
the desired immunosuppressive effect that affects not
only the anti-graft response, but the entire immune
response. Finding a way to establish donor-specific
immunological tolerance without the need for non-specific
immunosuppression remains one of the major goals in
transplantation medicine.
Mesenchymal stem cells (MSC) are multipotent
progenitors within the bone marrow capable of
differentiating into various cells and tissues, such as
chondrocytes, osteoblasts and adipocytes. MSC can be
isolated after ex vivo culture of the adherent mononuclear
bone marrow cell fraction. After ex vivo expansion, human
MSC have a fibroblastic-like morphology, and are
uniformly positive for SH2, SH3, CD29, CD44, CD71,
CD90, CD105, CD106, CD120a, CD124, and CD166 but
are negative for common hematopoietic markers like
CD14, CD45 or CD34. Human MSC express HLA-class I
and can be induced to express HLA-class II by IFN-γ.
However, MSC failed to induce proliferation of allogeneic
T-cells in in-vitro co-culture experiments. Further, MSC
can escape lysis from both cytotoxic T-cells and KIRmismatched NK cells.
MSC directly suppress ongoing immune response
through several mechanisms and thus demonstrate a
wide-ranging potential for the development of tolerogenic
strategies after transplantation. In a few attempts, the use
of MSC in solid organ transplantation has been examined
in animals. Under particular conditions, MSC were shown
to prolong the survival of skin and liver transplants in
primate and rats models. Controversial results were
observed in a rat heart transplantation model due to
different timing of MSC application as well as cumulative
number of cells administered.
In addition to their potential immunosuppressive effects,
the
potential
beneficial
effects
of
MSC
on
ischemia/reperfusion injury have been investigated in
animal models of kidney ischemia. In liver diseases, it
was also suggested that MSC administration could help
liver regeneration in animal models of terminal liver failure
or metabolic diseases. These potential beneficial effects
of MSC administration on the liver and the kidney have
not been tested and/or confirmed in clinical settings, but
no renal or hepatic deleterious effect of MSC
administration has been described so far either in animal
or in human trials.
Indeed, a possible effect of MSC on organ transplant
survival remains questionable, and justifies further
investigation. Four clinical trials (phase I-II) are now
investigating the safety and the feasiblility of autologous
MSC administration in patients with renal allograft
transplants (www.ClinicalTrials.gov). Clinical trials of MSC
in patients undergoing solid organ transplantation may
confirm the potential of these cells to provide a valuable
tool in transplantation medicine.
Email: [email protected]
Objectives
The present project aims at evaluating the safety and
tolerability of third party MSC administration after liver or
kidney organ transplantation.
Design
This study is a monocentric, open-label, prospective phase III study, including 20 liver and 20 kidney transplant recipients.
In a first step, after successful transplantation, 10 liver and 10
kidney
transplant
recipients
under
standard
immunosuppression (TAC-MMF-steroids + anti-IL2 antibodies
for the KT patients) will receive an intravenous infusion of
third party (healthy volunteers) MSC at a dose of 1.5-3.0
x106/kg on postoperative day 3  2. Except for the collection,
expansion and infusion of MSC, the clinical management of
the patients will not differ from that of routine transplantation.
In a second step, in all KT patients without rejection and with
normal creatinin and graft biopsy, steroid weaning will be
performed at month 3.
In LT patients without rejection episode and with normal graft
function and graft biopsy, weaning of immunosuppression will
be attempted at month 6; TAC will be progressively tapered
from month 6 to be stopped at month 9, and if the patient did
not develop rejection, MMF will be tapered from month 9 to
be stopped at month 12.
Inclusion
1. Liver and kidney recipients
Inclusion criteria
Male or female patients between 18 and 75 years of age, who
will undergo first KT or whole LT from a cadaveric (DBD or
DCD) organ donor; fertile female patients must use a reliable
contraception method;
Informed consent given by patient, for the complete (MSC +
follow-up) or partial (no MSC + follow-up) study
Successful liver or kidney transplantation, with demonstration
of organ function (improvement of INR in liver recipients and
of creatinine in kidney recipients) at 24-36h and normal graft
vasculature at Doppler examination
Exclusion criteria
Past history of malignant disease in organ donor or recipient,
with the exception of hepatocarcinoma within the Milan
criteria for the LT patients
Active uncontrolled infection (recipient and organ donor)
HIV or HCV positive (recipient or the organ donor)
EBV-negative recipient
Retransplantation
Combined transplantation
Living related transplantation or split liver transplantation
Autoimmune disease or expected impossibility to wean
immunosuppression (LT) or corticosteroids (KT) (recipient)
Endotracheal intubation (recipient)
Postoperative cardiovascular instability, active hemorrhage,
or any other serious clinical complication between
transplantation and evaluation for suitability for MSC infusion
(recipient)
For KT recipient: Panel reactive antibodies (PRA) >50%
(recipient)
2. MSC donors
The 20 study patients will be compared to a control group of
patients (10 liver and 10 kidney transplant recipients) that will
be selected with the same criteria that the study patients, but
who refused to be included in the study group while
accepting the supplementary blood collection necessary for
the immunological comparison between the two groups.
Endpoints
Primary
To evaluate the safety of MSC infusion after liver and kidney
transplantation:
1. infusional toxicity;
2. incidence of infections (bacterial, viral, fungal, parasitic)
and cancers (PTLD, others) at 6 months
Secondary
1. to evaluate patient and graft survivals;
2. to evaluate the effects of MSC on graft function (for LT:
bilirubin, INR, transaminases, GGT, at day 7, months 1, 3, 6,
9, 12; in KT: number of post transplant hemodialysis,
creatinine at day 7, months 1, 3, 6, 9, 12);
3. to evaluate biopsy-proven (Banff classification) rejection
rates at months 3, 6, 9, 12;
4; to evaluate the feasibility and safety of weaning or
decreasing immunosuppression;
5. to evaluate recipient’s immune function (T cell blood
populations (including T regs) by FACS, TREC quantification,
Vβ repertoire diversity, pathogen-specific T cells, anti-organ
donor HLA antibodies) at months 1, 2, 3, 4, 6, 9, 12;
6. to evaluate the potential development of anti-MSC donor
HLA antibodies at months 1, 3, 6, 12;
Inclusion criteria
Unrelated to the graft donor or recipient
Male or female
Age > 18 yrs
No HLA matching required
Fulfills generally accepted criteria for allogeneic HSC
donation
Informed consent given by donor
Exclusion criteria
Any condition not fulfilling inclusion criteria
Known allergy to lidocaine
Any risk factor for transmissible infectious diseases, in
particular HIV
Timeline
-First LT recipient was included in early 2012, inclusion should
be completed in late 2013, 6 months results in spring 2014
-First KT recipient included in summer 2013
Sponsors