Clinimacs Newsletter 2010

II

Customer report

Newsletter Vol. 10 No. 1/2010

CliniMACS®

Poster reportPoster report from the ASBMT 2010, USA

Products and applicationsMACS® GMP Products

Meeting minutesESC 2009, ASH 2009, EBMT 2010

2 CliniMACS Newsletter 1/2010

CliniMACS Newsletter online: www.miltenyibiotec.com/en/NN_503_CliniMACS_Newsletter.aspx

The CliniMACS® System components: Instruments, Reagents, Tubing Sets, and PBS/EDTA Buffer are manufactured and controlled under an ISO 13485 certified quality system. In Europe, the CliniMACS System components are available as CE-marked medical devices.In the USA, the CliniMACS System components including the CliniMACS Reagents are available for use only under an approved Investigational New Drug (IND) application or Investigational Device Exemption (IDE).CliniMACS® MicroBeads are for research use only and not for use in humans.MACS GMP Products are for research use and ex vivo cell culture processing only, and are not intended for human in vivo applications.The CryoMACS Freezing Bags are manufactured by Miltenyi Biotec GmbH and controlled under an ISO 13485 certified quality system. These products are available in Europe as CE-marked medical devices and are marketed in the USA under FDA 510(k) clearance.CliniMACS and MACS are registered trademarks and TheraSorb is a trademark of Miltenyi Biotec GmbH.All other trademarks mentioned in this document are the property of their respective owners and are used for identification purposes only.Copyright © 2010 Miltenyi Biotec GmbH. All rights reserved.

The CliniMACS® Newsletter is published by Miltenyi Biotec GmbH.Editors: Dr. Dirk Balshüsemann, Shamala S. Palaniappan Editorial board: Heike Lahnor, Dr. Michaela Malchow, Dr. Petra Bauer, Dr. Martina Simon, Dr. Katja Petry, Dr. Silke Schnell-Coopmans, Dr. Nanette von OppenGraphics & Layout: Miltenyi Biotec GmbH.Miltenyi Biotec GmbH, Friedrich-Ebert-Straße 68, 51429 Bergisch Gladbach, Germany.Phone +49 2204 8306-0, e-mail: [email protected].

4 Poster report Poster report from the 2010 annual meeting of the American Society for Blood and Marrow Transplantation (ASBMT) in Orlando, Florida, USA

7 Products and applications MACS® GMP Products Blood dendritic cells

11 Meeting minutes ESC 2009 ASH 2009 EBMT 2010

22 Frequently asked questions

26 Conference calendar

27 Fax reply form

In this issue

Contents

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 and subsequent isolation of viable antigen-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 cells play an important role in cell therapy concepts 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 describing this approach. Highlights and abstracts 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 symposium at the annual meeting of the European 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 BalshüsemannMiltenyi Biotec GmbH


Poster report

IntroductionThis poster report ties up data presented for the first 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-transplant prophylaxis, while disease-free and 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 allogeneic T cell–depleted stem cell transplantation 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, USAIn: 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-related mortality (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 approach to T cell depletion is safe and reproducible, 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.

In conclusion, these data support T cell depletion in the matched setting and suggest its extension to the matched unrelated setting.

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

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Customer report

• MACSGMPAntigens

• MACSGMPMedia

• MACSGMPCytokines

• CE-markedcellexpansionanddifferentiationbags

MACS GMP Cytokines, MACS GMP Media, and MACS GMP Antigens are for research use and ex vivo cell culture processing only, and are not intended for human in vivo applications. The products are manufactured and tested under a certified ISO 9001:2000 quality system and in compliance with relevant GMP guidelines and the recommendations of USP chapter 1043 on ancillary materials. In the USA, Cell Culture Bags are available for research use only. MACS is a registered trademark of Miltenyi Biotec GmbH. Copyright © 2010 Miltenyi Biotec. All rights reserved.

AdvancementsinclinicalapplicationMACS®GMPProducts

Miltenyi Biotec provides products and services worldwideVisit www.miltenyibiotec.com/local to find your nearest Miltenyi Biotec contact. www.macsgmp.com

7

Customer report

Advancements in clinical applicationsMACS® GMP Products MACS GMP Products enhance therapeutic procedures through cell stimulation, cell expansion and differentiation, and cryopreservation.

IntroductionCell-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 stimulationIt 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 differentiationThe same products are also used for cell expansion and differentiation, which may be performed after cell separation. 3. CryopreservationCryoMACS® 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 AntigensMACS 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 CytokinesMACS 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



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 MediaMACS 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 BagsCE-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


DC-based immune therapyDue 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 bloodTwo 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, in which PDC vaccination resulted in regression of treated and non-treated distant tumors, confirm this assumption.7,9

Pilot studies with blood DCs confirm safety and feasibilityRecently, 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 The CE-marking of CliniMACS CD304 (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.

References1. 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 #S05-00311. 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


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.


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

11

Meeting minutes

Meeting minutes2009/2010

ESC 2009, ASH 2009, EBMT 2010


Meeting minutes

Study design: Alster-MACS: Randomized study on the effect of CD133+´stem cells in chronic ischemic cardiomyopathy delivered intracoronary or intramyocardiallyMartin 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 2009August 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 aspectsGustav 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

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, f low 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-related complications were not observed. 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. One hundred and forty-two patients with coronary 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.”


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.

There are still many questions to be answered when considering stem cell treatment of the sequelae of myocardial infarction (MI). Hematopoietic stem cells seem to be the most effective type of cell but the 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 infarctionSamer 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 trial was designed to investigate the safety, 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

ASH 2009December 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: The data from 44 AML patients at eight participating centers demonstrated that infusion of 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 reported TCD studies represent single centers, 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 0303Steven 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


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 risk profile. The conditioning regimen consisted of 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 ≥5×10⁶ CD34+ cells/kg and <1.0×10⁵ CD3+ 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

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 by Prof. Martelli at a plenary session (abstract below) 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 is a viable strategy for the cure of acute leukaemia at high risk of relapse (Aversa et al. NEJM 1998; JCO 2005). As extensive T cell depletion is required to

prevent GvHD, the very narrow T cell repertoire 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 freshly isolated donor CD4+/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 received CD4+/CD25+ GMP immunoselected Tregs

Adoptive immunotherapy with Tregs prevents GvHD and favours immune reconstitution after HLA haploidentical transplants for hematological malignanciesMauro 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 IThiotepa 4 mg/kg/dayCyclophosphamide 35 mg/kg/dayFludarabine 40 mg/s qm/day

Days-3

Conditioning Tcons

Tregs CD 34+

No post transplant immuno suppression


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 median of 13 and 15 days, respectively (range: 11 to 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

Meeting minutes

EBMT 2010March 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 transplantationMassimo 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 patients with freshly purified Tregs before infusing high doses of conventional T cells in a haplo setting 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.”


Transplantation of CD3/CD19 depleted grafts in pediatric patients with hematological malignancies and non-malignant disordersPeter 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 leukemia was feasible and effective, showed reduced 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-SCTTobias Feuchtinger, Germany

NK cell therapy in hematologic malignanciesWing Leung, USA

Viral infections cause morbidity and mortality following hematopoietic stem cell transplantation. 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 matched grafts and who were suffering from either

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 determined by characterization of the killer Ig-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

Hematopoietic stem cell transplantation for severe autoimmune diseases – a program coming of ageJacob 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 inf lammation. 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 inf lammation 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 assess the risk-benefit of HSCT in scleroderma, SLE, MS, and Crohn’s disease. The randomized ASTIS (autologous stem cell transplantation international 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.”


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 [email protected]

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

Pro

cess

tim

e [m

in]

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 ProductsPeptides/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 TNF-α (# 170-076-103)

Both product groups will be continually expanded. 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.


SpeedupyourDCvaccinationBlooddendriticcell–basedimmunetherapy

CliniMACS®Reagents

MyeloidDCs CliniMACS CD1c (BDCA-1)/CD19 Complete Kit*

PlasmacytoidDCs CliniMACS CD304 (BDCA-4) Reagent*

The CliniMACS® System components: Reagents, Tubing Sets, Instruments, and PBS/EDTA Buffer are manufactured and controlled under an ISO 13485 certified quality system. In Europe, the CliniMACS System components are available as CE-marked medical devices. CliniMACS MicroBeads are for research use only and not for use in humans. MACS and CliniMACS are registered trademarks of Miltenyi Biotec GmbH. Copyright © 2010 Miltenyi Biotec GmbH. All rights reserved.

Miltenyi Biotec provides products and services worldwide. Visit www.miltenyibiotec.com/local to find your nearest Miltenyi Biotec contact. miltenyibiotec.com

BenefitfromCliniMACS®Technology• Highlypure• Clinical-gradedendriticcells(DC)•Directlyfromblood

* Available for research use only in the USA.

25

Notes:


Calendar

Conference calendarMeet 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

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Fax reply formCliniMACS® Newsletter Vol. 10 No. 1/2010

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EBMT 2010130-095-378

Abstract booklet, Miltenyi Biotec symposium“Cellular therapies – the next generation”

ESC Meeting 2009130-094-871 (booklet)130-094-872 (DVD)

Abstract booklet and DVD with all presentations, Miltenyi Biotec symposium“Study concepts and routes of administration in autologous stem cell therapy”

Product Catalog 2011/2012130-096-073

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Clinimacs Newsletter 2010

Technology

Transcript of Clinimacs Newsletter 2010