21st ISCT Annual Meeting
cohorts of ALS patients were treated via either intramuscular (IM) or intra-
thecal (IT) injections. In a recently completed phase 2a dose-escalating clinical
study (ClinicalTrials.gov Identifier: NCT01777646), three groups of ALS
patients were treated with increasing doses of MSC-NTF cells by both IM and
IT administration. In both studies, patients were followed for 3 months prior to
transplantation and for 6 months afterwards. Safety and various outcome
measures were monitored monthly, including ALS Functional Rating Score
(ALSFRS-R) and respiratory function (Forced Vital Capacity, FVC).
In both studies, no serious treatment-related adverse events were observed,
indicating that the treatment is safe, and in both studies subjects experienced
reduced mean rate of decline after treatment. Updated results of these studies
and a review of our ongoing US phase 2 clinical study (Clinicaltrials.gov
identifier NCT02017912) will be presented.
128
REDOSING STRATEGIES FOR MESENCHYMAL STEM CELL
THERAPY FOR CHRONIC OBSTRUCTIVE PULMONARY
DISEASE
A Patel1, J Tuma2, F Silva1
1 DJ Radel, GW Butler, JM Anderson, A Armstrong, D Padley, D Gastineau,
University of Utah, Salt Lake City, Utah, United States, 2Regenerative
Medicine, Maison de Sante, Lima, Peru
Background: Chronic obstructive pulmonary disease is both an obstructive
and inflammatory disease. Mesenchymal stem cell (MSC) therapy has shown
early promise to modulate inflammation and improve lung function. The
therapy has limitations resulting from cell loss and sub-optimal delivery. Even
when MSC therapy demonstrates a clinical benefit, there are questions related
to redosing if the clinical improvement decreases. Our goal was to develop a
redosing strategy for MSC therapy in patients with COPD.
Methods: Patients with severe COPD were randomized to receive either
MSCs, or MSCs with redosing after 6 months of treatment. All clinical events
along with pulmonary functions tests (FEV!/FVC) and oxygen requirements
were evaluated.
Results: Twenty patients were successfully enrolled in the study. All patients
were prior or recent smokers. There were no acute adverse events. All patients
were followed for one year. The MSC only group and MSC+redosing group
demonstrated improvement in pulmonary functions tests and oxygen require-
ment. However, the MSC redosing group continued to demonstrate benefit
over the MSC only group at 1 year.
Conclusion: MSC redosing therapy demonstrates safety along with promising
results in patients with chronic pulmonary obstruction disease. Larger trials
and follow up will be required to evaluate benefit and sustainability.
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130
BONE MARROW MESENCHYMAL STROMAL CELLS FROM
PATIENTS WITH ACUTE AND CHRONIC GVHD DEPLOY
NORMAL PHENOTYPE, DIFFERENTIATION PLASTICITY AND
IMMUNE-SUPPRESSIVE ACTIVITY
IB Copland1,2,4, M Qayed2, M Garcia3, J Galipeau1,2,4, E Waller1,4
1
Hematology and Oncology, Emory University, Atlanta, Georgia, United
States, 2Pediatrics, Emory University, Atlanta, Georgia, United States, 3Stem
Cell Transplantation and Immunotherapy, Emory Healthcare, Atlanta,
Georgia, United States, 4Winship Cancer Institute, Emory University, Atlanta,
Georgia, United States
The success of allogeneic hematopoietic stem cell transplantation (allo-HSCT)
is often limited by the development of acute and/or chronic graft versus host
disease (GVHD). The lack of effective therapies to treat steroid refractory
GVHD subjects has bolstered clinical evaluation of mesenchymal stromal cell
(MSC) therapies for GVHD. Currently, testing of MSCs for the treatment of
GVHD has exclusively been allogeneic despite emerging evidence that MSCs
lose their immunoprivileged status in vivo. We hypothesized that autologous
MSCs could be a viable alternative MSCs source for treating active GVHD.
MSCs were isolated and successfully expanded from the bone marrow of 12
volunteers (aged 2-55 years) who had allo-HSCT transplants and had devel-
oped GVHD. MSCs from subjects with GVHD demonstrated an initial lag in
growth compared to healthy controls, however this lag disappeared with
continued ex vivo expansion. Immunophenotype and mesodermal
S39
differentiation capacity of MSCs from GVHD patients were indistinguishable
to that of healthy control MSCs. In vitro immunomodulatory functional ana-
lyses also demonstrated that GVHD MSCs were equivalent to healthy control
MSCs with regards to dose dependently suppressing T-cell proliferation and
up-regulating Indoleamine 2,3-dioxygenase expression when primed with IFN-
gamma. STR chimerism analyses further demonstrated that MSCs expanded
from GVHD patients were exclusively recipient derived. Based upon these data
we conclude that recipient derived MSCs from patients with GVHD are
analogous to MSCs from healthy volunteers and represent a viable option for
clinical testing as an immunomodulatory option for symptomatic GVHD.
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132
A MANUFACTURING PLATFORM FOR ADIPOSE DERIVED
MESENCHYMAL STROMAL CELLS (AdMSC) SUPPORTING
CLINICAL TRIALS FOR DIVERSE INDICATIONS
A Dietz
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester,
Minnesota, United States
Mesenchymal stromal cells have great potential as a therapy for a variety of
diseases. We developed a manufacturing platform and the associated regulatory
and pre-clinical support for the rapid implementation of internal investigator-
initiated clinical trials for a number of diseases. Between July 2012 and Oct 2014,
we manufactured 64 AdMSC products from 60 patients for 5 clinical trials. The
disease indications include Amyotrophic Lateral Sclerosis, Multiple System At-
rophy, Atherosclerotic Renal Artery Stenosis, Fistulizing Crohn’s Disease, and
Ovarian Cancer. Aside from trial specific administration practices, the products
for all of these trials were manufactured on an identical platform consisting of
AdMSCs expanded in Advanced MEM (Gibco Life Technologies, Grand Island,
NY) supplemented with human platelet lysate (PLTMax, Mill Creek Life-
Sciences, Rochester MN). The median age of these patients was 58 years old
(range 18 - 80, SD 12) and median adipose biopsy was 0.3 grams (range 0.1 - 5.5,
SD 1.0). The dose of MSCs varied for each patient and within each study, but
using the calculated median population doublings, this platform could consis-
tently produce >500x106 cells in 16.5 days. These products had a median
doubling rate per day of 1.45 (range 0.97 - 1.92, SD 0.22). We have found no
correlation in the doubling times with age or BMI. Some patients received
products that were administered immediately post thaw, while others were given
after a four day recovery period in culture. The median doubling rate per day of
MSCs allowed to recover in culture was 0.72 (range 0.13 - 0.95, SD 0.19). Sixty
products were administered to 44 patients with no acute significant adverse
events. Overall we have demonstrated that MSCs can be consistently manufac-
tured from adipose tissue across a range of ages and disease groups.
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134
EFFECT OF MESENCHYMAL STEM CELL TREATMENT ON
AUTISM SPECTRUM DISORDER
L Tanchanco1,2, M De Vera1,2, S Bernal1, A Bengzon1,2
1
The Medical City Hospital, Pasig City, Philippines, 2Ateneo School of
Medicine and Public Health, Pasig City, Philippines
Autism spectrum disorder’s (ASD) definitive pattern of pathogenesis is still
undefined. Immune dysregulation and anti-brain antibody production has been
theorized. Mesenchymal stem cells (MSC) have been shown to possess
immunomodulatory characteristics. Our study aimed to determine the effect of
MSC infusion on ASD patients.
Five ASD patients (4-12 years) demonstrating slow progress despite maxi-
mizing conventional therapy and support services were given intravenous and
intraspinal infusions of minimally manipulated autologous bone marrow-
derived MSC under general anesthesia. Total dose of 1.5-2.8 x106 cells/kilo-
gram was given over 6 months. Primary outcome measured was safety,
observing for infusion-related adverse events. Secondary outcomes included
changes in scores on the Childhood Autism Rating Scale (CARS) and Aberrant
S40 Poster Abstracts
Behavior Checklist (ABC), and levels of IL-5, IL-10, IFN-g, TNF-a before
and after the 6-month period. Data was analyzed using Wilcoxon signed rank
test.
MSC infusion-related adverse events included headache, fever, rash and
pruritus, relieved with minimal intervention (paracetamol, antihistamine). One
patient had an asthma exacerbation, needing pre-treatment with bronchodila-
tors prior to the subsequent infusions. There was no recurrence of exacerba-
tions. All patients had a statistically significant decrease in CARS scores (lower
scores imply more appropriate behavior) with an average of 25.7% improve-
ment (p¼0.05). There was an average improvement of all the patients on the
ABC, but only on the domain of hyperactivity was it significant (29.3%,
p¼0.05). Overall decrease in IL-5 and TNF-a was not statistically significant.
Bone marrow-derived autologous MSC infusion is relatively safe for patients
with ASD. Patients appeared to exhibit more appropriate behavior after the
therapy. Further trials involving more patients are needed to better charac-
terize the effects of MSC on ASD.
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137
REPORTING OF MESENCHYMAL STROMAL CELL (MSC)
MANUFACTURING AND CHARACTERIZATION IN A
SYSTEMATIC REVIEW OF MSC TREATMENT FOR PRE-
CLINICAL MODELS OF SEPSIS
KJ Sullivan1, L McIntyre1,2, M Lalu1,3, SH Mei4, D Moher1,5, D Fergusson1,
J Marshall6, B Winston7, K Walley8, M Jazi9, DJ Stewart4,10
1 conducted by two authors independently with standard methods. Data analyses
Clinical Epidemiology Program, The Ottawa Hospital Research Institute,
Ottawa, Ontario, Canada, 2Department of Medicine (Division of Critical
Care), University of Ottawa, Ottawa, Ontario, Canada, 3Department of
Anesthesiology, University of Ottawa, Ottawa, Ontario, Canada, 4Regenerative
Medicine Program, The Ottawa Hospital Research Institute, Ottawa, Ontario,
Canada, 5Department of Epidemiology and Community Medicine, University
of Ottawa, Ottawa, Ontario, Canada, 6Department of Surgery and Critical
Care Medicine, Keenan Research Centre of the Li KaShing Knowledge
Institute, St. Michaels Hospital, University of Toronto, Toronto, Ontario,
Canada, 7Departments of Critical Care Medicine, Medicine and Biochemistry
and Molecular Biology, University of Calgary, Calgary, Alberta, Canada,
8 67% (95%CI, 61-71%) and 47% (95%CI, 40-55%), respectively. With respect
Centre for Heart Lung Innovation, University of British Columbia, Vancouver,
British Columbia, Canada, 9University of Ottawa, Ottawa, Ontario,
Canada, 10Department of Cell and Molecular Medicine, University of Ottawa,
Ottawa, Ontario, Canada
Rationale: MSCs represent an exciting potential treatment for sepsis, however
manufacturing heterogeneity may affect their potency and therapeutic efficacy.
We described reporting of MSC manufacturing and human MSC character-
ization in a systematic review of MSCs for the treatment of pre-clinical sys-
temic sepsis.
Methods: A systematic search of electronic databases was conducted up
to March 25, 2014. We collected data on MSC manufacturing (culture
medium, growth factors, passages, population doublings, viability and
preparation) and characterization of human MSCs according to the Inter-
national Society of Cellular Therapy’s (ISCT) recommended criteria
(plastic adherence, tri-lineage differentiation, and cell surface antigen
expression).
Results: Twenty-five studies were included. Ninety-two percent (n¼23) re-
ported the MSC culture medium; the most common medium was DMEM
(48% n¼12). Eighty percent (n¼20) of studies reported MSC growth pro-
moting factors; fetal bovine serum was used most commonly (76% n¼19) with
concentrations ranging from 9% to 20%. MSC passage numbers were reported
in 72% (n¼18) of studies and ranged from 3 to 15. One study (4%) reported on
MSC population doublings and viability, while 28% (n¼7) reported on MSC
preparation (fresh versus cryopreserved). Of the nine studies that used human
MSCs, none met all 3 ISCT MSC characterization criteria: 33% (n¼3) re-
ported on plastic adherence, 22% (n¼2) on MSC differentiation, 44% (n¼4)
and 56% (n¼5) reported on positive and negative cell surface antigen expres-
sion, respectively.
Conclusions: The reporting of MSC manufacturing and human MSC char-
acterization was sub optimal. Standardized reporting may enhance the ability of
researchers to repeat experiments and conduct meta-analyses to examine het-
erogeneity in treatment effects according to these variables.The use of guide-
lines, such as ARRIVE (Animal Research: Reporting of In Vivo Experiments)
for pre-clinical studies, may improve standardized reporting.
138
THERAPEUTIC EVALUATION OF MESENCHYMAL STEM CELL
INJECTION FOR GRAFT-VERSUS-HOST DISEASE: A SINGLE
ARM META-ANALYSIS
HW Yim1, H Jeong1, S-G Cho3, Y-s Cho2, S Jeong4, H-b kim1, I-H Oh5
1
Preventive Medicine, The Catholic University of Korea, Seoul, Korea (the
Republic of), 2Seo-myeon Branch Office of the Community Health Center,
Uljin-gun, Korea (the Republic of), 3Department of Hematology, Catholic
Blood and Marrow Transplantation Center, Seoul St. Mary’s Hospital, Seoul,
Korea (the Republic of), 4Medical Library, St. Mary’s Hospital, Seoul, Korea
(the Republic of), 5Catholic High-Performance Cell Therapy Center &
Department of Medical life science, College of Medicine, The Catholic
University of Korea, Seoul, Korea (the Republic of)
MSC used as a treatment modality to patients with steroid-resistant GVHD.
To systematically review the literature and provide an overview of reported
both efficacy and safety outcomes of MSC for GVHD.
A comprehensive search of the literature was carried out in July 2014. Core
data base was used to identify relevant studies since their inception up to July
2014. Efficacy oucomes reported both overall and complete responses during
the follow-up period. Safety outcomes reported into three categories: SAE,
death, and TRM. Study selection, data extraction, and quality assessment were
were performed using Comprehensive Meta-analysis version 2.2. (Biostat Inc.,
Englewood, NJ). We performed random effects model meta-analyses to eval-
uate pooled incidence rates of treatment responses and adverse events. Also, we
conducted subgroup analysis in term of follow-up period, population age, cell
type, and company sponsored or investigator initiative researches to explore the
source of heterogeneity.
359 Potentially eligible articles were identified of which eventually 17 ful-
filled our inclusion and exclusion criteria. Treatment option for GVHD con-
sists of infusion of third-party, HLA-unrelated, or related bone marrow donor
MSCs. The pooled incidence rate of both overall and complete responses were
to pooled incidence rates of occurring SAEs, death, and treatment related
mortality which were reported by the authors 37% (95%CI, 31-44%), 35%
(95%CI, 27-45%), and 13% (95%CI, 10-21%), respectively during a mean
follow-up of 10 months.
The published data suggest that MSCs appear to be well-tolerated for ste-
roid-resistant GVHD patients as a treatment modality based on single arm
clinical studies. However, clinical benefits and safety of MSC need further
investigation and reevaluation through placebo-controlled phase III clinical
trials.
139
PRESERVATION OF QUALITY AND EFFICACY OF HUMAN
PLATELET LYSATE PATHOGEN REDUCED WITH
PHOTOSENSITIZING ADDITIVE-FREE THERAFLEX UV-
PLATELETS TECHNOLOGY
S Viau1, L Chabrand1, F Goudaliez2, C Sumian2, B Delorme1
1
Biotherapy Division, Macopharma, Mouvaux, France, 2Transfusion Division,
Macopharma, Tourcoing, France
We recently developed and characterised a standardised and clinical grade hu-
man Platelet Lysate (hPL) that constitutes an advantageous substitute for foetal
bovine serum for human mesenchymal stem cell (hMSC) expansion required in
cell therapy procedures, avoiding xenogenic risks (virological and immunolog-
ical) and ethical issue. Because of the progressive use of pathogen reduced (PR)
labile blood components, we evaluated the impact of the novel procedure
THERAFLEX UV-Platelets for pathogen reduction on hPL quality