3. 3
Editorial
Editorial
Dear Colleagues,
I am pleased to present the latest issue of our
CliniMACS® Newsletter.
At Miltenyi Biotec it has been our focus, for many
years, to offer innovative products for biomedical
and preclinical research. Within just over twenty
years since the company began, this has resulted
in over 1,000 products for cell separation, analysis,
cell culture, and molecular characterization.
Close co-operations and numerous contacts with
researchers all over the world have enabled our
scientists to stay tuned to the latest developments
in areas of biomedical research with potential for
improved cellular therapies.
The requests and advice from translational as well
as clinical researchers are the key to our efforts
to bring innovative treatment concepts ‘from
bench to bedside’. In this respect, we are proud
to announce that recently several MACS® GMP
Products have been added to our clinical grade
product portfolio. These products include GMP
Cytokines for cultivation and differentiation of
cells and GMP Antigens—as recombinant protein
or peptide pool—for efficient in vitro stimulation
andsubsequentisolationofviableantigen-specific
T cells. Read more on page 7.
Research into regulatory T cells (Tregs) has been
one of the key topics in immunology during recent
years. It was found that these immunomodulatory
cellsplayanimportantroleincelltherapyconcepts
for tolerance induction. Today, in the context of
haploidentical transplantation, Tregs are already
under clinical evaluation. The rationale is to allow
infusion of donor T cells for improved immune
reconstitution without increasing the risk of
GvHD. In this issue, you will find the summary
of a presentation from the recent ASH meeting
describingthisapproach.Highlightsandabstracts
are on page 15.
Results of a US multicenter trial (BMT CTN
protocol 0303), which investigated the use of
T cell–depleted grafts after myeloablative
conditioning for acute myeloid leukemia, were
presented at the same ASH meeting. The
investigators did not find an increased rate of
relapses despite the profound T cell depletion, but
they did find a remarkable reduction in acute and
chronic graft-versus-host disease.
As in previous years, we hosted a satellite
symposiumattheannualmeetingoftheEuropean
Society of Cardiology in Barcelona, Spain. Several
trials were presented in that session and we
are particularly proud of having started the
first phase III trial investigating the effects of
autologous bone marrow–derived stem cells in
cardiac disease. An excerpt is on page 12.
Finally, I would like to draw your attention to the
list of upcoming congresses and symposia on page
26. Take the opportunity to meet us there and to
discuss your recent findings and future plans in
cellular therapy!
With kind regards,
Dr. Dirk Balshüsemann
Miltenyi Biotec GmbH
4. 4 CliniMACS Newsletter 1/2010
Poster report
Introduction
Thisposterreporttiesupdatapresentedforthefirst
time by Richard O’Reilly at the annual meeting of
the American Society of Hematology (ASH) 2009
in New Orleans, Louisiana, USA.
At ASH, the results were shown from the BMT
CTN protocol 0303 phase II multicenter trial
which utilized a uniform technique of CD34+
selection with the CliniMACS device in adult
patients with AML in first or second complete
remission (refer to page 15). The outcome data of
44 patients demonstrated that infusion of CD34-
enriched stem cells from a matched, related donor
resulted in low transplant-related mortality, low
incidence of relapse, and low incidences of graft-
versus-host disease (GvHD) in the absence of any
post-transplantprophylaxis,whiledisease-freeand
overall survival were excellent.
For this poster, the authors compared their BMT
CTN protocol 0303 trial with the concomitant
BMT CTN protocol 0101 phase III multicenter
trial, whose aim was the comparison of two
antifungal prophylaxis medications after
allogeneicTcell–depletedstemcelltransplantation
with pharmacologic immunosuppression, post
transplantation.
Using the same eligibility criteria from BMT
CTN protocol 0303 trial as selection criteria for
the protocol 0101 patient population, 102 patients
from the latter trial were selected as controls for
the protocol 0303 trial. Outcomes were assessed
after 6 and 12 months of follow-up (refer to table 1)
and included disease-free survival (DFS), overall
From the poster board: Poster report
from the 2010 annual meeting of the
American Society for Blood and Marrow
Transplantation (ASBMT) in Orlando,
Florida, USA
In: Biol. Blood Marrow Transplant 2010, 16: S268 (abstract 297) Comparative effectiveness analysis
of CD34+
selected, T cell–depleted (TCD), HLA-matched sibling grafts on allogeneic hematopoietic
cell transplantation for patients with acute myeloid leukemia (AML) in complete remission.
Presented by Pasquini M. et al., on behalf of the Blood and Marrow Transplant Clinical Trials Network.
survival(OS),transplant-relatedmortality(TRM),
and rates of acute and chronic GvHD. Relapse,
DFS, OS, and TRM were similar in both cohorts.
However, there was a notable difference in the
rates of GvHD between the two cohorts.
For acute GvHD the TCD group showed a rate of
20% versus 38% in the non-TCD group at 100 days
post-transplant. The difference in the occurrence
of chronic GvHD was even more significant: 19%
versus 47% at one year after transplantation.
With this comparative analysis the authors found
similar outcomes in TCD and non-TCD sibling
allografts in AML, and showed that a standardized
approachtoTcelldepletionissafeandreproducible,
and leads to a reduction in debilitating GvHD
without increasing relapse rates. The fact that
this reduction was achieved in the absence of any
post-transplant immune suppression suggests that
patients receiving CD34-selected TCD grafts will
enjoy an improved quality of life.
Inconclusion,thesedatasupportTcelldepletionin
the matched setting and suggest its extension to the
matched unrelated setting.
5. 5
Poster report
Outcome TCD [%] (95% CI)
n=44
non-TCD [%] (95% CI)
n=102
p-value
Disease-free survival at 6 months 81 (66–90) 75 (68–87) NS
Relapse at 12 months 19 (6–32) 19 (11–26) NS
Transplant-related mortality at 12 months 19 (6–31) 22 (14–30) NS
Engraftment at 28 days 100 (86–100) 90 (79–100) NS
Acute GvHD II-IV at 100 days 20 (9–32) 38 (28–47) 0.046
Chronic GvHD at 12 months 19 (7–32) 47 (35–58) 0.008
Overall survival at 12 months 74 (57–85) 69 (59–77) NS
Figure 1: Acute GvHD at 100 days post-transplant.
Table 1: Follow-up data for 6 and 12 months. NS = not significant.
Figure 2: Chronic GvHD at one year post-transplant.
Acute GvHD at 100 days post transplant
0
5
10
15
20
25
30
35
40
non-TCD TCD
Probability (%)
Chronic GvHD at 1 year post transplant
0
5
10
15
20
25
30
35
40
45
50
non-TCD TCD
Probability (%)
0
5
10
15
non-TCD TCD
Probability (%)
Chronic GvHD at 1 year post transplant
0
5
10
15
20
25
30
35
40
45
50
non-TCD TCD
Probability (%)
Probability(%)
Probability(%)
7. 7
Customer report
Advancements in clinical applications
MACS® GMP Products
MACS GMP Products enhance therapeutic procedures through cell stimulation, cell expansion and
differentiation, and cryopreservation.
Introduction
Cell-based therapies are an emerging treatment
option in a variety of diseases, for example,
solid tumors, hematologic malignancies, and
transplantation-related complications. The
basis for the increase of therapies arises from an
improved understanding of cellular function and
culture of precursor cells like monocytes. The
understanding of the plasticity of these precursor
cells allows maturation and manipulation of
cells in vitro. Miltenyi Biotec provides a range of
solutions to support the manufacturing process
of cell-based therapies. From the core process
to additional steps, we have systems and GMP
Products to enhance the therapeutic procedure
through:
1. Cell stimulation
It may be necessary to stimulate the cells between
leukapheresis and cell separation. Our range of
MACS GMP Antigens, Cytokines, Media, and
Cell Culture Bags offers an ideal platform to
complete the process.
2. Cell expansion and differentiation
The same products are also used for cell expansion
and differentiation, which may be performed after
cell separation.
3. Cryopreservation
CryoMACS® Freezing Bags offer the option for
cryopreservation after leukapheresis or prior to
administration to the patient.
Quality: crucial in advancing
clinical applications
The quality of the starting materials dramatically
influences the outcome of the cellular product.
All MACS GMP Products are manufactured
in our state-of-the-art GMP facility in Teterow,
Germany in standardized and strictly controlled
industrial processing steps. They are designed
according to the recommendations of the United
States Pharmacopeia, chapter 1043 on ancillary
materials for cell-, gene-, and tissue-engineered
products. Consequently, they are free of human
and animal-derived components, and product
specifications are confirmed by batch-specific
certificates of analysis to ensure consistency of
quality.
MACS GMP Products
MACS GMP Antigens
MACS GMP Antigens are designed for in vitro
stimulation of antigen-specific T cells and for
antigen loading of dendritic cells (DCs). MACS
GMP Antigens are offered in two different
configurations: as a recombinant protein in
its natural configuration, or as a peptide pool
(PepTivator®) consisting of mainly 15-mer
peptides, covering the whole sequence of the
antigen. Both products efficiently stimulate
CD4+
and CD8+
T cells in vitro and cause the
production of the effector cytokine IFN-γ by the
antigen-specific T cells. IFN-γ secretion permits
enrichment of antigen-specific effector/memory
T cells by using CliniMACS Cytokine Capture
System (IFN‑gamma). The viral antigens pp65
(HCMV) and hexon (AdV) are offered as MACS
GMP Products and our MACS GMP Antigen
product portfolio is constantly growing.
MACS GMP Cytokines
MACS GMP Cytokines are recombinant human
cytokines for research applications or ex vivo
cell culture, for example, the ex vivo generation
of human DCs from enriched CD14+
monocytes.
MACS GMP Cytokines are lyophilized without
carrier protein or preservatives. Reliable
reconstitution and performance is assured by an
optimized formulation. Lot-specific certificates
confirm identity, molecular mass, specific activity,
sterility, purity, and endotoxin content, as well
as host-cell DNA and protein content. MACS
GMP Recombinant Human IL-4, GM-CSF, IL-1β,
TNF-α, and IL-6 constitute a comprehensive
portfolio of cytokines for ex vivo DC generation.
Products and applications
8. 8 CliniMACS Newsletter 1/2010
Products and applications
For additional applications, IL-3 and FGF-2 are
already available and IL-2, IL-7, and IL-15 will
soon expand the fast-growing range of MACS
GMP Cytokines.
MACS GMP Media
MACS GMP Media are serum-free, defined
formulations optimized for cultivation and
expansion of cells ex vivo.
The high quality DendriMACSTM
Medium has
been designed for optimal and standardized
cultivation of human DCs and the generation of
monocyte-derived DCs from CD14+
monocytes.
MACS GMP Media are manufactured without
phenol red and are supplied in bags.
A tailored medium for optimal cultivation and
expansion of human T and regulatory cells will
follow soon.
Cell Culture Bags
CE-marked Cell Culture Bags were developed for
in vitro culture, differentiation, and expansion
of human cells from heterogeneous hematologic
cell populations in a functionally closed
system. The unique Cell Expansion Bag has a
compartmentalized culture chamber with two
easy-to-open seals. This allows for expandable
culture volume as cell numbers increase during
culture period. There is no need to change
the culture vessel, which reduces the risk of
contamination. Cell Expansion Bags for volumes
up to 100 mL are on offer. Also available are Cell
Differentiation Bags with one culture chamber.
They come in three different volumes (100, 250,
and 500 mL). Volumes of 1,000 and 3,000 mL will
be available soon.
9. 9
Products and applications
DC-based immune therapy
Due to their key role in initiation and regulation of
innate and adaptive immune response, dendritic
cells (DCs) are widely used in clinical trials to
induce effective anti-tumor immunity—with
moderate efficacy.1
Recently, however, a double-
blind, placebo-controlled phase III study in
advanced prostate cancer was able to show
extended median survival after vaccination
with autologous tumor-antigen-loaded, antigen-
presenting cells (APCs).2
Remarkably, in contrast
to most other DC-based studies, in which ex vivo-
generated, monocyte-derived DCs (MoDCs) had
been used, in this case APCs were directly isolated
from blood. Properties of the native cells and the
combination of different APCs may be the key to
success.
Distinct DC subsets in blood
Two major populations of DCs are distinguished
in human peripheral blood, myeloid DCs (MDCs)
and plasmacytoid DCs (PDCs). The different
subsets seem to be functionally specialized.
Whereas MDCs, as MoDCs, have a strong T cell
stimulatory capacity,3
PDCs are characterized by
production of high amounts of type I interferon
(IFN) after activation via Toll-like receptors
(TLRs).4-6
Type I IFNs enhance innate and
adaptive immune response by initiating a series
of cellular events involving sequential activation
of NK cells, B cells, monocytes, MDCs, and CD8+
T cells.7
PDCs are thus believed to be crucial for
a strong and effective anti-tumor therapy.8
Pre-
clinical experiments using tumor mouse models,
inwhichPDCvaccinationresultedinregressionof
treated and non-treated distant tumors, confirm
this assumption.7,9
Pilot studies with blood DCs confirm
safety and feasibility
Recently, Figdor, de Vries, and co-workers
performed the first phase I PDC vaccine study
in late-stage melanoma patients. They proved
safety and feasibility, and showed induction
of an antigen-specific immune response.10
The promising immunological results will be
published soon. Safety and feasibility of antigen-
pulsed MDCs in clinical studies on the treatment
of melanoma and prostate cancer was shown
earlier.11,12
Direct isolation of blood DCs using
the CliniMACS® System
TheCE-markingofCliniMACSCD304(BDCA-4)
Reagent has now extended the product line
for clinical-scale enrichment of DCs in
combination with the CliniMACS System.
PDCs, as well as MDCs, can now be easily
isolated directly from blood with high purity
and reproducible yield, according to distinct
expression of specific surface markers CD304
(BDCA-4) on PDCs and CD1c (BDCA-1)
on MDCs.13
Using the CliniMACS Instrument,
separation is performed in a closed, automated
system. Remarkably, cells are immature upon
isolation and mature overnight in culture. Long
culture periods, as required for the differentiation
and maturation of MoDCs, are therefore avoided.
The opportunity to enrich PDCs and MDCs
directly from blood in a clinical setting thus
reveals new perspectives for DC-based immune
therapy.
References
1. Melief, C.J. (2008) Immunity 29: 372–383.
2. Higano, C.S. et al. (2009) Cancer 115: 3670–3679.
3. Jefford, M. et al. (2003) Blood 102: 1753–1763.
4. Liu, Y.J. (2005) Annu. Rev. Immunol. 23: 275–306.
5. McKenna, K. et al. (2005) J. Virol. 79: 17–27.
6. Schreibelt, G. et al.(2010) Cancer Immunol. Immunother. 59:
1573–1582.
7. Liu, C. et al. (2008) J. Clin. Invest. 118: 1165–1175.
8. Kim, R. et al. (2007) Immunology 127:149–157.
9. Aspord, C. et al. (2010) PLoS ONE 5: 10458–10458.
10. de Vries, I.J.M. et al. (2010) 11th International Symposium on
Dendritic Cells (DC2010): Abstract #S05-003
11. Prue, R. L. et al. (2007) 5th Int. Meeting on DC vaccination
(DC2007): Abstract #P090.
12. Davis, I. D. et al. (2005) Proc. Amer. Assoc. Cancer. Res. 46:
Abstract #3466.
13. Dzionek, A. et al. (2000) J. Immunol. 165: 6037–6046.
New perspectives for DC-based immune
therapy: blood dendritic cells
10. 10 CliniMACS Newsletter 1/2010
Customer report
Product Application Availability Order no.
Plasmacytoid dendritic cells – CliniMACS CD304 (BDCA-4) Cell Enrichment
CliniMACS CD304 (BDCA-4)
Reagent, CE
Enrichment of CD304 (BDCA-4)+
PDCs in a clinical setting Europe1)
278-01
CliniMACS CD304 (BDCA-4)
MicroBeads
Enrichment of CD304 (BDCA-4)+
PDCs in a
pre-clinical setting
USA2)
, CAN,
AUS
291-01
Myeloid dendritic cells – CliniMACS CD1c (BDCA) Cell Enrichment
CliniMACS CD1c (BDCA-1)/
CD19 Complete Kit, CE
Kit contains all components needed for
enrichment of CD1c (BCDA-1)+
MDCs in a clinical setting
Europe1)
740-03
CliniMACS CD1c (BDCA-1)-
Biotin for Research Use
Enrichment of CD1c (BCDA-1)+
MDCs in conjunction with
CliniMACS Anti-Biotin Reagent and CliniMACS CD19
Reagent for pre-clinical settings
USA2)
, CAN,
AUS
255-01
1) Not available in the US.
2) In the US only for research use.
Products and applications
CliniMACS® Products for direct isolation of blood DCs
The MACS® GMP Product portfolio for dendritic cells
Product Order no.
DendriMACS GMP Medium 170-076-302
MACS GMP Recombinant Human IL-3 170-076-110
MACS GMP Recombinant Human IL-4 170-076-101
MACS GMP Recombinant Human GM-CSF 170-076-112
MACS GMP Recombinant Human IL-1ß 170-076-102
MACS GMP Recombinant Human TNF-α 170-076-103
MACS GMP Recombinant Human Il-6 170-076-104
MACS GMP HCMV pp65 – Recombinant Protein 200-076-100
MACS GMP PepTivator HCMV pp65 170-076-109
MACS GMP PepTivator AdV5 Hexon 170-076-106
12. 12 CliniMACS Newsletter 1/2010
Meeting minutes
Study design: Alster-MACS: Randomized study on the effect of
CD133+´
stem cells in chronic ischemic cardiomyopathy delivered
intracoronary or intramyocardially
Martin Bergmann, Germany
Treatment of cardiomyopathies with autologous
bone marrow stem cells by the intracoronary
or intramyocardial route has been shown to be
safe. The efficacy of these treatments has been
somewhat limited, however. Two strategies that
might improve this effectiveness involve the
identification of the most effective cell type and
improvement in the route of administration.
ESC 2009
August 29 to September 2, 2009, Barcelona, Spain
Satellite symposium: Study concepts and routes of administration in autologous stem cell therapy.
The following summary elucidates compiled information on surgical and interventional concepts
to investigate autologous stem cell therapy approaches in cardiovascular diseases.
Cellular therapy – present aspects
Gustav Steinhoff, Germany
The last ten years have been marked by new
developments in the field of cardiac therapies,
especially in cases of heart failure. One of those
developments is the transplantation of autologous
stem cells, although there are still many questions
to be answered with respect to the source of the
graft (blood, bone marrow, skeletal muscle,
adipose tissue, embryonic stem cells), and the
route of administration (local or systemic). It is
also unclear whether bone marrow–derived cells
should be used in an unmodified state or whether
they should be enriched for the antigen133. There
are considerable regulatory issues that have to be
resolved before human trials can take place and
these require investment of considerable time and
effort before approval can be granted.
This Satellite Symposium focuses on the
application of CD133+
bone marrow stem cells in
cardiac disease.
“… identification of the
most effective cell type and
improvement in the route of
administration.”
13. 13
Meeting minutes
Patients with refractory angina treated with peripheral blood–derived
stem cells using the transendocardial injection route
Pilar Jimenez-Quevedo, Spain
A randomized, blinded, multicenter controlled
trial has been designed to assess the safety and
efficacy of transendocardial injection of selected
CD133+
cells in patients with refractory angina
without any option of standard revascularization.
Patients will be treated with G-CSF for 4 days
prior to leukapheresis and enrichment of CD133+
cells. Crossover will be carried out 6 months
after the CD133+
cells have been administered
by trans-endocardial injection with the aid of
electromechanical cardiac mapping.
The results of this study will shed light on the
treatment of this subset of patients who still
show symptoms despite maximum conventional
therapy.
A randomized, single-blinded, clinical trial
has been designed to examine the efficacy of
autologous CD133+
stem cells in the treatment of
patients with chronic ischemic cardiomyopathy.
The trial will compare the intracoronary route
with the intramyocardial route with intensive
follow-up for one year, and endpoints at 6 and 12
months. The endpoints will be assessed on global
ejection fraction, cardiac performance, 6 minute–
walk test and a quality of life questionnaire.
“The aims of stem cell transplantation are to
improve the level of neovascularization and to
regenerate damaged myocardial tissue”.
Intramyocardial transplantation of bone marrow stem cells for improvement
of post-infarct myocardial regeneration in addition to bypass surgery:
a controlled, prospective, randomized, double-blinded, phase III,
multicentric trial (PERFECT trial)
Gustav Steinhoff, Germany
The preparation of CD133+
cells as a cell-
based product should be standardized and the
component cells characterized by, for example,
flow analysis, preclinical models, and other
phenotypic analyses.
Previous phase I and II clinical trials of bone
marrow stem cells in the treatment of chronic
ischemia following cardiac infarction and
subsequent coronary artery bypass grafting
(CABG) have shown that there is a positive effect
on left ventricle ejection fraction (LVEF) and
improved survival compared to CABG alone;
graft-relatedcomplicationswerenotobserved.The
PERFECT trial is a phase III placebo-controlled,
double blind, multicenter trial designed to
investigate whether the intramyocardial injection
of autologous, bone marrow-derived CD133+
cells
results as a functional benefit for CABG patients.
Onehundredandforty-twopatientswithcoronary
artery disease after myocardial infarction, with an
indication for CABG and LVEF values between
25% and 40%, will be enrolled in the study and
randomized to either enriched autologous CD133+
stem cell or placebo. The study period is 6 months;
LVEF assessed by magnetic resonance imaging
(MRI) is listed as both primary and secondary
endpoints. Secondary endpoints will include
echocardiography, physical exercise testing, and
a quality of life assessment.
Recent evidence suggests that the heart can
undergo repair processes in adulthood and that
vasculogenesis may not be exclusive to embryonic
development. Revascularization of tissue
following a cardiac infarct is one of the aims of
conventional therapy, although 12% of all patients
referred to a coronary artery disease clinic are
refractory to further revascularization because
they have diffuse coronary disease, small distal
vessels, recurrent stent stenosis, chronic total
occlusion, or co-morbidities. Several secondary
medicinal treatments are available but there is a
lack of evidence that these have any benefit to the
patient. Other treatment strategies, such as laser
treatment or neurostimulation, are associated
with inconsistent data in the clinical situation.
“… there is a positive effect
on left ventricle ejection
fraction (LVEF) and improved
survival compared to
CABG alone; graft-related
complications were not
observed.”
“The results of this study will
shed light on the treatment
of this subset of patients who
still show symptoms despite
maximum conventional
therapy.”
“Two strategies that might
improve this effectiveness
involve the identification of the
most effective cell type and
improvement in the route of
administration.”
14. 14 CliniMACS Newsletter 1/2010
Meeting minutes
Intramyocardial application of stem cells in combination with transmyocardial
laser revascularization in CABG patients
Hans-Michael Klein, Germany
as laser or shock wave treatment of the affected
tissue, are required to improve functionality of
the graft. A trial has recently been initiated that
investigates intramyocardial injection of CD133+
cells purified by CliniMACS in MI patients with
ejection fraction values between 15% and 35%.
Preliminary results demonstrate improvements
in cardiac function and quality of life. The
6 month follow-up shows a significant increase in
LVEF measures by echocardiography. The MRI
estimation of LVEF is more subject to variability,
mainly as a result of patient excitability. It also
appears that the level of scarring in the myocardial
tissue has a negative effect on the outcome of stem
cell therapy.
Therearestillmanyquestionstobeansweredwhen
considering stem cell treatment of the sequelae of
myocardial infarction (MI). Hematopoietic stem
cellsseemtobethemosteffectivetypeofcellbutthe
question remains whether cell processing should
be carried out parallel to surgery in the operating
theater or in a separate laboratory. A further
question concerns the route of administration:
on the one hand, intravenous injection is clearly
ineffective and intracoronary injection appears
to have limited effectiveness. On the other hand,
transendocardial and transepicardial injection
during surgery appear to be equally effective.
There is also some debate about whether intra-
operative revascularization procedures, such
Comparison of intracoronary CD133+
bone marrow stem cells to placebo in
cardiac recovery after myocardial infarction
Samer Mansour, Canada
Although bone marrow stem cell grafts represent
a promising approach to the treatment of the
infarcted myocardium, use of heterogeneous
preparations of bone marrow cells have led to
variable clinical outcomes, possibly because the
different cell types in the graft interfere with each
other.
Experimental evidence suggests a role for
CD133/34+
stem cells in the biological repair
of the damaged myocardium through their
ability to enhance vasculogenesis and myocyte
regeneration. A pilot trial of CD133+
stem cells
administered by the intracoronary route resulted
in an improvement in the LV ejection fraction in
the treated patients when compared to controls
matched for ejection fraction, size of infarct, and
its localization. However, angiographic findings
indicated an increase in restenosis in the treated
group during the four month follow-up period so
a double-blind, randomized, placebo-controlled
trialwasdesignedtoinvestigatethesafety,efficacy,
and functional effect of intracoronary injection of
enriched autologous CD133+
cells to patients with
an LVEF less than 50% and following stented
acute myocardial infarction. Enrollment for this
trial is still ongoing but the first 20 patients have
already shown a significant improvement in LVEF
after four months of follow-up. The data so far
indicates that intracoronary injection of CD133+
bone marrow stem cells is safe and has significant
beneficial effects on LVEF.
“The data so far indicates
that intracoronary injection
of CD133+
bone marrow
stem cells is safe and has
significant beneficial effects
on LVEF.”
“Preliminary results indicate
that the quality of life has
improved notably compared
to the preoperative data.”
15. 15
ASH 2009
December 5 to 8, 2009, New Orleans, Louisiana, USA.
Here, we report on two selected presentations from the ASH meeting. The latter, describing the
use of regulatory T cells in a mismatched transplantation setting, was elected for the presidential
session. Both presentations were discussed at a press conference.
Oral presentation 1: Monday, December 7, 2009;
4:30 p.m. (Ernest N. Morial Convention Center):
Highlights:Thedatafrom44AMLpatientsateight
participatingcentersdemonstratedthatinfusionof
CD34+
-enriched stem cells from a matched related
donor results in low transplant-related mortality,
low incidence of relapse, and excellent disease-free
and overall survival. The low incidences of acute
and chronic GvHD in the absence of any post-
transplant prophylaxis were particularly encour-
aging, as the absence of this complication highly
improves the patient’s quality of life.
A full-paper publication comparing these data to
another transplant study will come out shortly.
Adapted from abstract published online at
http://ash.confex.com/ash/2009/webprogram/
Paper18537.html.
Abstract 655 : Allogeneic hematopoietic cell trans-
plantation (HCT) is the most effective means to
prevent relapse in patients (pts) with AML in
complete remission (CR). However, quality of life
and overall survival (OS) are often affected by
both acute and chronic graft-versus-host disease
(GvHD). GvHD is most effectively prevented by
ex vivo T cell depletion (TCD) of the allograft, but
has been limited in its use by logistical difficulties,
lack of an FDA-approved method, and concerns
regarding potential risk of graft rejection, post-
transplant infections, and leukemic relapse. Most
reportedTCDstudiesrepresentsinglecenters,mul-
Meeting minutes
HLA-identical sibling-matched, CD34+
-selected, T cell–depleted peripheral blood
stem cells following myeloablative conditioning for first or second remission acute
myeloid leukemia (AML): Results of Blood and Marrow Transplant Clinical Trials Network
(BMT CTN) protocol 0303
Steven M. Devine, MD, Robert J. Soiffer, MD, Marcelo C. Pasquini, MD, Shelly Carter, Parameswaran N. Hari, MD,
MRCP, MS, Stephanie DeVore, Anthony Stein, Hillard M. Lazarus, MD, Charles Linker, MD, Edward A. Stadtmauer,
MD, Carolyn A. Keever-Taylor, PhD , and Richard J O’Reilly, MD
16. 16 CliniMACS Newsletter 1/2010
Meeting minutes
tiple disease types, and processing methods with
varying degrees of TCD, all of which affect out-
come. Therefore we designed a trial using a single
processing method providing extensive TCD that
did not require post transplant GvHD prophy-
laxis involving adult patients with AML in first or
second CR. We hypothesized that the undesired
side effects of TCD HCT would be reduced if com-
bined with a conditioning regimen that was highly
immunosuppressive and anti-leukemic. The pri-
mary objective was to achieve a disease-free sur-
vival (DFS) rate at 6 months (mos) post transplant
that exceeded 75%. Secondary objectives included
assessments of engraftment, transplant-related
mortality (TRM), GvHD, relapse, and perfor-
mance of a single TCD method (CD34+
cell selec-
tion using the CliniMACS device) at participating
centers. From 10/2005 to 12/2008, 47 patients were
enrolled and 44 transplanted at 8 different centers.
Median age was 48.5 years (range 21–59) with 28
female and 16 male pts. Of 37 AML CR1 patients,
49% had an unfavorable cytogenetic or molecular
riskprofile.Theconditioningregimenconsistedof
hyperfractionated total body irradiation (1375cGy
in 11 fractions) with partial lung shielding, thiote-
pa (10 mg/kg), cyclophosphamide (120 mg/kg),
and rabbit antithymocyte globulin (2.5 mg/kg).
The donors, all HLA-identical siblings, were given
G-CSF for mobilization and scheduled to undergo
at least two leukapheresis procedures to ensure a
graft with a high CD34+
cell content. All allografts
were CD34-enriched and were targeted to contain
≥5×10⁶CD34+
cells/kgand1.0×10⁵CD3+
cells/kg.
The median CD34+
and CD3+
doses achieved
were 8.1×10⁶/kg (range2.4–46.2) and 0.07×10⁵/kg
(range 0.01–0.85), respectively. The majority (81%)
of patients received the targeted CD34+
cell dose
and no patient received 1.0×10⁵ CD3+
cells/kg.
No pharmacological GvHD prophylaxis was given
post-transplant. There were no significant tox-
icities related to infusion of the CD34-enriched
allografts. The most common grade 3–5 regimen-
related toxicities included grades 3 or 4 mucositis
(39%) and grades 3–5 pulmonary abnormalities
(11%). Only one patient experienced hepatic veno-
occlusive disease. All patients engrafted rapidly
with a median time to neutrophil recovery (ANC
500/µL) of 11 days (range 9–19). There was one
secondary graft failure. The assessed outcomes
are shown below.
The absolute peripheral CD4+
cell count remained
on average below 200 µL until day +365. Donor cell
chimerism increased in the CD3+
cell compart-
ment through day +365. There were 14 deaths. The
most common causes of death were relapse N=5
and pulmonary toxicity N=4. The median follow-
up of survivors is 489 days range 96-776. There
was no difference in OS or DFS for pts above or
below the median age of 48.5 years. We conclude
that TCD HCT–following myeloablative chemo-
radiotherapy can be performed in a multicenter
setting using a single TCD method without addi-
tional post-transplant prophylaxis with excellent
DFS and OS‚ consistent engraftment‚ low TRM
and low incidence of relapse even in patients with
unfavorable risk AML in CR1. The low incidences
of acute and chronic GvHD in the absence of post-
transplant prophylaxis were particularly encour-
aging. A follow-up study of TCD HCT in AML
recipients of unrelated donor allografts is being
planned by the BMT CTN.
Estimate (95% confidence interval)
Outcome 100 days 6 months 12 months
Acute GvHD II-IV 20.5% (8.7–23.3%)
Acute GvHD III-IV 4.5% (0–10.6%)
Chronic GvHD 17.7% (5.8–29.6%)
Extensive chronic GvHD 7.6% (0–15.7%)
TRM 17.8% (5.8–29.8%)
Overall relapse 18.2% (5.9–30.5%)
Relapse 1st CR 9.6% (0–19.8%)
Relapse 2nd CR 64.3% (27.5–100%)
DFS 64.0% (46.5–77.1%)
DFS 1st CR 72.1% (53.0–84.6%)
OS 74.3% (57.3–85.4%)
17. 17
Customer reportMeeting minutes
Oral presentation 2: Sunday, December 6, 2009;
2:45 p.m. (Ernest N. Morial Convention Center):
Highlights:
An innovative strategy using CliniMACS-enriched
regulatory T cells (CD4+
/CD25+
) might improve the
outcome of patients, who undergo haploidentical
stem cell transplantation. This is the conclusion
from an ongoing clinical trial, which was presented
byProf.Martelliataplenarysession(abstractbelow)
and even discussed at a press conference. Based
on successful animal models, this first-in-man
phase I/II trial evaluates the impact of regulatory
T cells on graft-versus-host disease–prevention and
immunological immune reconstitution.
Preliminary data of 28 patients demonstrate that
by using the CliniMACS to enrich for regulatory
T cells, transfusing high numbers of donor T cells,
up to 2×106
/kg can be allowed.
Remarkably, a very low incidence of graft-versus-
host disease was observed in the 26 evaluable
patients, whilst speed of post-transplant immune
recovery and the incidence of CMV reactivation
was improved compared to previous studies. Two
patients were not evaluated due to a different
protocol. These preliminary results raise hope that
with longer follow-up of this treatment method will
lead to reduced infection-related mortality and thus
improve overall survival.
Finally, this study may open up new prospects for
the adoptive transfer of T regulatory cells not only
in the field of hematology but for other indications,
for example, to induce specific immunological
tolerance in the field of organ transplantation and
autoimmune diseases.
Adapted from abstract published online at
http://ash.confex.com/ash/2009/webprogram/
Paper18555.html.
Transplantation of large numbers of highly
purified CD34+
cells from haploidentical relatives
isaviablestrategyforthecureofacuteleukaemiaat
high risk of relapse (Aversa et al. NEJM 1998; JCO
2005). As extensive T cell depletion is required to
prevent GvHD, thevery narrow Tcellrepertoire in
the inoculum delays recovery of immune response
against pathogens, leading to a high incidence of
infection-related deaths. Thus the key challenge
is to improve immune recovery by administering
allogeneic donor T cells without causing graft-
versus-host disease (GvHD). Preclinical studies
demonstrated that freshly isolated or ex vivo
expanded T regulatory cells (Tregs) could be
used to control GvHD-following bone marrow
transplantation. The present phase I/II clinical
trial evaluated the impact of early infusion of
freshlyisolateddonorCD4+
/CD25+
Tregs,followed
by an inoculum consisting of donor mature T cells
(Tcons) and positively immunoselected CD34+
cells, on GvHD prevention and immunological
reconstitution. Twenty-two patients (10 male; 12
female; median age 40.5, range, 21 to 60) with
AML (n=17; 8 in CR1 at high risk, 7 in ≥CR2, and
2 in relapse), ALL (n=4; 3 in CR1; 1 in relapse) and
1 with high grade NHL in relapse were enrolled
from September 2008 onwards. The conditioning
regimen consisted of 8Gy single fraction TBI,
thiotepa (4 mg/kg×2), fludarabine (40 mg/m2
×4),
and cyclophosphamide (35 mg/kg×2). All patients
receivedCD4+
/CD25+
GMPimmunoselectedTregs
Adoptive immunotherapy with Tregs prevents GvHD and favours immune
reconstitution after HLA haploidentical transplants for hematological malignancies
Mauro Di Ianni, Franca Falzetti, Alessandra Carotti, Adelmo Terenzi, Elisabetta Bonifacio, Yair Reisner,
Andrea Velardi, Franco Aversa, and Massimo F Martelli
Figure 1: Treatment schedule: After conditioning, patients
were infused with escalating doses of Tregs, followed three
days later by immune-selected CD34+
cells together with
individual doses of donor mature T cells.
8 Gy T B I
Thiotepa 4 mg/kg/day
Cyclophosphamide 35 mg/kg/day
Fludarabine 40 mg/s qm/day
Days
-3
Conditioning Tcons
Tregs CD 34+
No post
transplant
immuno
suppression
18. 18 CliniMACS Newsletter 1/2010
Customer report
(CliniMACS, Miltenyi Biotec) (21/22 2×10⁶/kg bw;
1/22 1×10⁶/kg bw). Three days later they received
positively immunoselected CD34+
cells (median
8.2×106
/kg, range 5.0–19.1) together with Tcons
(16/22 1×106
/kg bw; 4/22 0.5×106
/kg bw; 2/22 did
not receive Tcons). Immunoselected CD4+
/CD25+
Tregs (purity 91.5%±4.5) consisted of CD25high
25.6%±11.2; CD25int 57.4%±5.9; CD25low
8.5%±6; FoxP3 64%±1; CD127 14.9%±13.7
(mean±SD). As suggested by in vitro immuno-
suppressive assays and by immunophenotypic
analysis, the contaminating cells in the Treg
fraction were 50% of the CD25int and 100% of
the CD25low, so that the infused Tregs:Tcons
ratio was established at 1:1.5. No post-transplant
prophylaxis against GvHD was used and 20/22
patients were engrafted. Neutrophils reached
1×10⁹/L at a median of 15 days (range; 11 to 39
days). Platelets reached 25×10⁹/L and 50×109
/L at
medianof13and15days,respectively(range:11to
48 days, and 13 to 60 days). All engrafted patients
showed persistent full donor-type chimerism in
peripheral blood and bone marrow. Strikingly,
no GvHD was observed in 17/20 valuable patients,
2/20 developed grade I cutaneous self-limited
untreated GvHD and 1/20 developed grade III
GvHD. This patient had received the fewest
Tregs. Six patients died (1 bacterial sepsis, 2 VOD,
1 fungal pneumonia, 1 CNS aspergillosis, and
1 GvHD/systemic toxoplasmosis). In contrast with
our previous experience, the speed of immune
recovery was enhanced. The CD4 and the CD8
counts reached, respectively, 50/µL medianly on
days 34 (range: 19 to 63 days) and 24 (range: 15
to 87); 100/µL medianly on days 47 (range: 28 to
100 days) and 34 (range: 19 to 95); 200/µL on days
70 (range: 41 to 146 days) and 61 (range: 21 to 95).
We also observed a rapid development of a wide
T cell repertoire and detection of high frequencies
of specific CD4+
and CD8+
for opportunistic
pathogens such as Aspergillus, Candida, CMV,
ADV, HSV, VZV, and Toxoplasma. In KIR
ligand–mismatched transplants, speed of NK cell
reconstitution/maturation and size of donor
versus recipient alloreactive NK cell repertoires
were preserved (Ruggeri et al. Science 2002).
In conclusion, in the setting of haploidentical
transplantation, infusion of freshly purified
Tregs makes administration of a high dose of
T cells feasible for the first time. This strategy
provides a long-term protection from GvHD
and robust immune reconstitution. Treg-based
cellular therapy may represent an innovative
strategy to improve the outcome of haploidentical
transplants.
Meeting minutes
19. 19
Meeting minutes
EBMT 2010
March 21 to 24, 2010, Vienna, Austria
Satellite symposium: Cellular therapy – the next generation. A very interactive symposium saw
the latest in cellular therapy being discussed with highlights on allogeneic stem cell transplants,
haploidentical stem cell transplants, T cell and NK cell therapy.
Adoptive immunotherapy with Tregs and Tcons hastens immune
reconstitution without triggering GvHD in HLA haploidentical
transplantation
Massimo F. Martelli, Italy
Preclinical models have indicated that
CD4+
/CD25+
regulatory T cells (Tregs) aid graft-
versus-tumor activity while suppressing GvHD.
The speaker described the immuno-magnetic
enrichment of Tregs in a fully automated system
that yielded 2–4×10⁶/kg Tregs. Treating leukemia
patientswithfreshlypurifiedTregsbeforeinfusing
highdosesofconventionalTcellsinahaplosetting
resulted in a low incidence of GvHD but there
was no cross-inhibition of Tcons responses to
pathogens. By enhancing immune reconstitution,
adoptive transfer of Tregs and Tcons significantly
reduced the risk of CMV reactivation.
An allogeneic stem cell transplant is usually
required in acute lymphoblastic leukemia patients
at risk of relapse. The probability of finding a
matched sibling donor is low so a haploidentical
stem cell graft is often the only option, with the
associated problem of graft-versus-host disease
(GvHD). This problem has been countered in the
past by depletion of T cells but this, in turn, has
resulted in a high incidence of infection-related
complications. The principal objective of clinical
research is thus to improve immune recovery
without causing GvHD.
“By enhancing immune
reconstitution, adoptive
transfer of Tregs and Tcons
significantly reduce the risk
of CMV reactivation.”
20. 20 CliniMACS Newsletter 1/2010
Transplantation of CD3/CD19 depleted grafts in pediatric patients
with hematological malignancies and non-malignant disorders
Peter Bader and Thomas Klingebiel, Germany
period of between 1 and 61 months. Transplant-
related mortality was caused by toxicity (n=4),
GvHD (n=1) and adenoviral infection (n=1) in
four patients with malignant disease. Only those
leukemia patients who were in remission at the
time of transplantation had a 70–80% probability
of a 3-year survival. NK receptor-ligand mismatch
also increased the probability of survival amongst
all patients. T cell and NK regeneration was
apparent within 40 days of transplantation.
The speaker concluded that the haploidentical
engraftment in adolescents and young adults with
leukemiawasfeasibleandeffective,showedreduced
acute toxicity and rapid immune regeneration.
Successful haploidentical stem cell transplan-
tation is associated with an aggressive regimen of
immune depletion and very high doses of puri-
fied peripheral stem cells containing insignifi-
cant numbers of T or B cells. One of the recent
advancements in stem cell transplantation was
the realization that the use of alloreactive NK cells
reduces GvHD, enhances immune reconstitution
and aids graft-versus-leukemia activity. The
speaker reviewed a prospective trial involving
60 patients (10 with non-malignant disease) aged
from 0.6 to 27.2 years who were transplanted with
stem cells depleted immuno-magnetically with
CD3/19 MicroBeads and assessed over a follow-up
T cell immunotherapy for viral complications post-SCT
Tobias Feuchtinger, Germany
NK cell therapy in hematologic malignancies
Wing Leung, USA
Viral infections cause morbidity and mortality
followinghematopoieticstemcelltransplantation.
An effective T cell response appears to be essential
for clearance of the virus, and adoptive transfer
of pathogen-specific donor T cells has become
increasingly important for patients with viral
infections who lack specific T cell responses.
The speaker described a trial of adoptive T cell
transfer in 59 patients (41 with leukemia) who
had previously received haplo, mismatched, or
matchedgraftsandwhoweresufferingfromeither
The speaker noted the four most significant
adverse events associated with bone marrow
transplantation: graft-versus-host disease, disease
relapse, infection, and graft rejection. An ad-
vantage of NK transplantation is that all these
parameters are reduced. The NK donor is best
determinedbycharacterizationofthekillerIg-like
receptor (KIR) whereby a KIR match appears
to increase the likelihood of relapse and a KIR
mismatch to reduce it. A large-scale enrichment
adenovirus or cytomegalovirus infection. Donor
peripheral blood mononuclear cells (PBMC) were
stimulated with appropriate viral antigen for 16
hours before CD4+
and CD8+
cells were isolated
and infused into the patient. Follow-up showed
that virological and clinical improvement
correlated with in vivo CMV and ADV T cell
responses. It appears that adoptive T cell transfer
of antigen-specific T cells represents an effective
second-line treatment for viral complications
after SCT.
of NK cells was described, which resulted in high
CD56+
cell purity and less than 1% T and B cells.
These NK cells showed extensive proliferative
activity in vivo. A BMT and KIR mismatch NK cell
transplant of infant leukemia patients improved
survival from 0% to 65%. A trial of single parental
KIR mismatch NK grafts with ten AML patients
who had completed standard chemotherapy
resulted in an estimated survival of 50–60% over
a period of four years.
“My Dad’s NK cells are great.
Now I’m in remission.”
Meeting minutes
“… haploidentical
engraftment in adolescents
and young adults with
leukemia was feasible and
effective, showed reduced
acute toxicity and rapid
immune regeneration.”
“… adoptive T cell transfer
of antigen-specific T cell
represents an effective
second-line treatment
for viral complications
after SCT.”
21. 21
Hematopoietic stem cell transplantation for severe autoimmune
diseases – a program coming of age
Jacob M. Van Laar, UK
The key treatment goal in autoimmune disease
is prevention of end-organ damage but many
conditions remain incurable despite new treat-
ment paradigms and biologicals. Two of the
aims of hematopoietic stem cell transplantation
(HSCT) are to induce and maintain regulation
and to abrogate inflammation. The level of
progression-free survival following HSCT is
related to the underlying disease. The outcome
of HSCT in MS is affected by age and number
of years since diagnosis: younger and sooner has
the best prognosis following HSCT. HSCT in RA
suppresses inflammation but is not curative,
whereas in SLE, HSCT results in a rapid
improvement in clinical parameters. There are a
large number of trials ongoing within Europe to
assesstherisk-benefitofHSCTinscleroderma,SLE,
MS, and Crohn’s disease. The randomized ASTIS
(autologousstemcelltransplantationinternational
scleroderma) trial compares CliniMACS CD34 –
selected SCT versus cyclophosphamide therapy
in 150 patients. Here, a higher event-free survival
is expected in the SCT arm in comparison to
the control arm. Current evidence suggests that
HSCT is a treatment option for carefully selected
patients with a high-risk, but not end-stage, severe
autoimmune disease for whom no conventional
therapy exists.
Meeting minutes
“… HSCT is a treatment
option for carefully selected
patients with a high-risk,
but not end-stage, severe
autoimmune disease for
whom no conventional
therapy exists.”
22. 22 CliniMACS Newsletter 1/2010
FAQs
Which types of tubing sets can be used for a
CD3 or a combined CD3/CD19 depletion*?
Both the CliniMACS Depletion Tubing Set and
the CliniMACS Tubing Set LS are suitable for a
CD3 or CD3/CD19 depletion. The graph below
illustrates that for products containing up to
4.5×10⁹ labeled cells the processing time for both
tubing set types is comparable.
FAQs
However, with higher numbers of labeled cells
the CliniMACS Depletion Tubing Set is clearly
time-saving (example for 20×10⁹ labeled cells: The
depletion process using the CliniMACS Depletion
Tubing Set takes 1.25 hours versus 5 hours if using
the CliniMACS Tubing Set LS).
21–40×10⁹ labeled cells can only be processed in one procedure when using the CliniMACS Depletion Tubing Set.
We would greatly
appreciate your feedback.
Please e-mail us at
macs@miltenyibiotec.de
Processing time LSTS versus DTS
Total number of labeled cells [×10⁶]
Processing time LSTS versus DTS
0
50
100
150
200
250
900 2.250 3.375 4.500 9.000 13.500 18.000
total number of labeled cells [x10
6
]
Process time [min]
LSTS DTS
Processtime[min]
23. 23
FAQs
What can be done to optimize a CD3
or a combined depletion*?
· Processing apheresis products directly
after harvest.
· Minimizing the number of potentially
interfering apheresis-related factors (e.g.
granulocytes, platelets) effectively.
· Using Fc-receptor blocking prior to CD3
labeling in order to minimize non-specific
binding.
· Ensuring that all cells are in contact with
the reagent during labeling.
· Safely determining the sample parameters for
the CliniMACS procedure. Considering all
CD3+
and CD19+
cells for input of “frequency
of labeled cells”, not only real T and B cells.
· Determining the frequency of labeled cells
directly before the labeling procedure is
started.
· Determining the remaining T and B cells with
an appropriate flow cytometry protocol (rare
cell analysis), e.g., Schumm, Cytotherapy 2006,
Koehl, Int. J. Hematol. 2008, or Miltenyi Biotec
special protocol 54.
Do the CryoMACS® Freezing Bags contain
any latex?
No, all CryoMACS Freezing Bags are latex-free.
MACS® GMP Products provide integrated
solutions for cell separation and cell culture.
Which products are currently available?
Currently available MACS GMP Products
Peptides/proteins:
MACS GMP HCMV pp65 – Recombinant
Protein (# 200-076-100)
MACS GMP PepTivator HCMV pp65
(# 170-076-109)
MACS GMP PepTivator AdV5 Hexon
(# 170-076-106)
Cytokines:
MACS GMP Recombinant Human GM-CSF
(# 170-076-112)
MACS GMP Recombinant Human FGF-2
(# 170-076-107)
MACS GMP Recombinant Human IL-1β
(# 170-076-102)
MACS GMP Recombinant Human IL-3
(# 170-076-110)
MACS GMP Recombinant Human IL-4
(# 170-076-101)
MACS GMP Recombinant Human IL-6
(# 170-076-104)
MACS GMP Recombinant Human TNF-α
(# 170-076-103)
Bothproductgroupswillbecontinuallyexpanded.
Different types of cell culture bags intended for
in vitro expansion, differentiation, or cultivation
are already part of the MACS GMP Product
portfolio with cell culture media to be added
later.
* The CliniMACS CD3/CD19 Reagent combination is not available
in the USA.
26. 26 CliniMACS Newsletter 1/2010
Calendar
Conference calendar
Meet us at the booth!
Date Congress Webpage
December 4-7, 2010 ASH-American Society of Hematology, Orlando, FL, USA www.hematology.org
January 24-27, 2011 Arab Health 2011, Dubai www.arabhealthonline.com
February 17-21, 2011 BMT Tandem Meetings (ASBMT, CIBMTR), Honolulu, Hawaii,
USA
www.asbmt.org
March 24-25, 2011 Cellular Therapy 2011 - 6th Intl Symposium on the Clinical
Use of Cellular Products, Erlangen, Germany
www.cellular-therapy.de
April 3-6, 2011 EBMT-European Group of Blood and Marrow
Transplantation, Paris, France
www.congrex.ch/ebmt2011
27. 27
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CliniMACS® Newsletter Vol. 10 No. 1/2010
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EBMT 2010
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Abstract booklet, Miltenyi Biotec symposium
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130-094-871 (booklet)
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Abstract booklet and DVD with all presentations, Miltenyi
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“Study concepts and routes of administration in autologous
stem cell therapy”
Product Catalog 2011/2012
130-096-073
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