Newsletter Vol. 9 No. 1/2009

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1 CliniMACS Newsletter Vol. 9 No. 1/2009 Customer reports Validation of CryoMACS Freezing Bags Products and applications New CryoMACS Freezing Bags Meeting minutes Treg user meeting, ESC 2008, ASH 2008, EBMT 2009, BMT 2009

2 Contents In this issue 4 Customer reports Validation of CryoMACS Freezing Bags 9 Products and applications New CryoMACS Freezing Bags 13 Meeting minutes Treg user meeting ESC 2008 ASH 2008 EBMT 2009 BMT Upcoming satellite symposia 29 Frequently asked questions 30 Conference calendar 31 Fax reply form CliniMACS Newsletter online: The CliniMACS System components: Instruments, Reagents, Tubing Sets, and PBS/EDTA Buffer are manufactured and controlled under an ISO 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. The CryoMACS Freezing Bags are manufactured by Miltenyi Biotec GmbH and controlled under an ISO certified quality system. These products are available in Europe as CE-marked medical devices. FDA 510(k) notification currently under review by US FDA. CliniMACS, CryoMACS, 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 2009 Miltenyi Biotec GmbH. All right 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. Uwe Hattenhorst Graphics & Layout: Miltenyi Biotec GmbH. Miltenyi Biotec GmbH, Friedrich-Ebert-Straße 68, Bergisch Gladbach, Germany. Phone , 2 CliniMACS Newsletter 1/2009

3 Editorial Editorial We also work actively at providing innovative tools for clinical research and are proud to announce an extended CliniMACS Product line for cell separation. There are new GMP products such as cytokines and growth factors as well as the new CryoMACS Freezing Bags. The latter is discussed further in our products and applications segment. Dear colleagues, Cellular therapies continue to pave the way for treatment strategies and clinical research to expand the horizon for potential applications. We at Miltenyi Biotec are excited to be a part of the process of discovering new medical frontiers. The clinical business department at Miltenyi Biotec strives to provide products and services to the biomedical and clinical research industries and personally, as a physician, it gives me great pleasure to be part of a team that caters to clinicians in this exciting field. The clinical business department is now defined as units of autoimmunity, virology, oncology, graft engineering, hematology, tissue regeneration, TheraSorb, and new products such as CryoMACS Feezing Bags. With this structure, the units are hopefully more distinguishable and have the ability to propel medical research more efficiently. Our partnership with you, our customer, brings our innovations into practice. In this issue of our CliniMACS Newsletter, we present in the customer report segment a validation report by Dr. Mike Watts on our new CryoMACS Freezing Bags which provide safety in cryopreservation. The CryoMACS Freezing Bags are detailed further in the newsletter. In addition, our usual forum for discussion via our satellite symposia is highlighted here. In this issue we summarize presentations from the Treg user meeting, the ESC 2008, ASH 2008, the EBMT 2009, and the BMT We encourage you to mark your calendars for the conferences we have highlighted in the upcoming symposia segment which promises to hold an excellent line up of speakers and provide a good platform for discussions. Please find on the last page of the CliniMACS Newsletter a fax reply form if you would like to receive further information on any of the products or applications featured. We welcome suggestions for our future CliniMACS Newsletters and would be grateful for your insights. We hope you enjoy this issue of the newsletter and find the information and ideas useful for your applications. Dr. med. Darline Cheatham-Seitz Global Head Clinical Business 3

4 Customer report Evaluation of CryoMACS Freezing Bags for the cryopreservation of stem cell harvests in clinical transplantation Dr. Michael Watts, expert on hematology and stem cells. Currently serving in the Research Department of Oncology, University College London, London. thawed, the overwrap pouch is cut open and the freezing bag set up for infusion. The suitability of a bag for clinical use can only properly be assessed by testing it at all of these stages. The design criteria established for freezing bag use at UCLH were used to make the initial evaluation of the CryoMACS Freezing Bag. The cryopreservation properties of CryoMACS Freezing Bags were assessed using the non-target CD34 + cell-poor fraction obtained from clinical CD34 + cell enrichment procedures as detailed below. The cells were processed, frozen-stored, and thawed in the same way as routine clinical harvests. Direct comparisons were then made of thaw cell viability and colony counts for each brand of freezing bag. Introduction CryoMACS Freezing Bags consist of a freezing bag with an integrally attached tubing set and an overwrap bag, which provides additional containment for the freezing bag. This report concerns a study to evaluate Cryo- MACS Freezing Bags in the clinical setting that was carried out at the Wolfson Cellular and Gene Therapy Unit, University College London Hospitals (UCLH) by Stuart Ings, Carmen Balsa, Andrew Antonio, and Mike Watts. In current clinical cryopreservation methods, stem cells are diluted in a dimethyl sulfoxide (DMSO)- based cryoprotectant solution in autologous plasma and/or human serum albumin, dispensed into freezing bags, frequently in many centres sealed in a protective overwrap pouch, and frozen in stainless steel cassettes. The cells are then stored at an ultra low temperature, usually below 130 C, most commonly in the vapor phase of nitrogen at 190 C. When the cells are issued frozen to the nursing staff, they are transferred in a portable nitrogen vapor phase (or dry ) shipper. The cells are then thawed by submersion in a water bath set to between +37 C to +40 C. Once completely Materials and methods Design evaluation study Three brands of freezing bag used in routine practice at UCLH were compared with the CryoMACS design using the characteristics listed below: Handling at liquid (vapor) nitrogen temperatures ( 190 C) Compatibility with available heat-sealing equipment Fully protected access ports to maintain sterility before spiking Internal spike port guards to prevent spike damage to bag Individually sterile packed containers Double-sterile wrapping, convenient for clean-room use Compatibility with current freezer storage system Sterile overwrap bag included for easier cleanroom handling Integral label pocket for a detachable identity label (that can be affixed to the patients infusion chart) 4 CliniMACS Newsletter 1/2009

5 Customer report Full traceability from a lot number imprinted on the primary container Standard ( ml) and small (10 20 ml) capacity primary containers. Cellular cryopreservation efficiency The cryopreservation efficiency, in terms of preservation of cell viability and clonogenic function, was compared for two currently available brands of bag and the CryoMACS Freezing Bag. CD34 + cells constitute about 1% of the cells in a typical stem cell harvest and contain the great majority of progenitor cells. Clinical-scale CD34 + cell enrichment is used to produce highly purified CD34 + cells for transplantation and the depleted CD34 + cell fraction of the stem cell harvest is normally discarded. This non-target fraction was used to evaluate the freezing bags in this study. All donors gave informed signed consent. The CD34 + cell depleted non-target fraction from the CliniMACS CD34 + cell enrichment procedures was adjusted with donor plasma and used to represent the fresh pre-freeze harvest for the purpose of this study. The following viable cell and progenitor tests were carried out on each sample: 1) White cell count (WBC) 2) Flow cytometric CD34 + /CD45 + assay with 7-aminoactinomycin D (7AAD, stains dead cell nuclei) as a viability marker 3) 14-day colony assays for granulocytemonocyte-colony forming cells (GM-CFC) and burst-forming unit erythroid cells (BFU-E) All colony assays were performed using a methylcellulose based medium (Miltenyi Biotec). The CD34-poor fraction was diluted in cryoprotectant according to the normal clinical protocol and 88 ml aliquots of the cells were added to each of the freezing bags from each manufacturer. Overwrap bags from manufacturer B were used to enclose the primary containers from manufacturers A and B, and the CryoMACS Freezing Bags used with their own overwrap bags. The bags were frozen at 196 C and then transferred to mechanical storage freezers at 140 C until thaw testing. Before thawing, the bags were placed in a vapor shipper at 190 C for 1 2 hours to reproduce the normal procedure for delivery of frozen cells to the patients. Each bag was then thawed by submersion in a water bath at 37 C. The tests of WBC, CD34 + cell count, 7AAD%, and colony assays were repeated for each bag in order to determine thaw progenitor recovery counts and yields. At every stage each freezing bag was inspected for any evidence of any leaks or cracks during handling, freezing, and thawing. Results Compatibility with design criteria Although not included in the current cryopreservation study, the Wolfson Unit had previously used a freezing bag from another supplier, manufacturer C. This product is included in the design specification (table 1) for completeness. All of the four freezing bag brands were found to be compatible with use at 190 C, with standard heat sealing equipment, and with standard clinical freezer storage canisters. All freezing bags have integral patient identity label pockets, full lot traceability, and were available for the most commonly used cell product volumes of ml and ml size (table 1). In use, all of the freezing bag brands provided secure, leak free connections with standard, liquid transfer plastics using either the integral spike ports or luer-lock connections. The compliance with infusion or blood bag requirements for access ports was not judged satisfactory for bags purchased from manufacturer A because the two port spike inner membranes were not adequately protected with a secure seal and the spike guards were too short to prevent potential damage to the bag wall during spiking. In addition, sterile cell processing could not be assured with this brand, or with the bags from manufacturer C, because they were not supplied in sterile packaging. Efficacy of cell cryopreservation Three peripheral blood stem cell harvests from two healthy donors were processed to provide three non-target fractions from CD34 + enrichments as outlined above. The three pre freeze harvest viable cell count and progenitor counts are shown in table 2. The mean and range of thaw results from each triplicate set of freezing bags of each brand are shown for comparison. There was a modest loss in total white cell numbers but the thaw viability was high for all 27 freezing bags tested with the lowest percentage at 94.5%. 5

6 Customer report In the first experiment, the CD34 + cell yield appears lower for the CryoMACS Freezing Bags but this is not reflected in the clonogenic progenitor yields and is more likely to be a reflection of lower precision in the measurement of the very low CD34 + cell numbers in the first pre-freeze harvest that resulted from a very efficient CliniMACS CD34 + cell enrichment procedure (table 2). The thaw recovery of viable white cells, GM-CFC, and BFU-E clonogenic cells for each brand of freezing bag are summarized in figure 1 (A C). No significant differences were seen between any of the freezing bag brands on test. Design criteria Manufacturer A Manufacturer B Manufacturer C CryoMACS Freezing Bag Handling at low temperature Yes Yes Yes Yes Sealing equipment compatibility Yes Yes Yes Yes Protected access ports No Yes Yes Yes Internal spike port guards No Yes Yes Yes Individual sterile packaging No Yes Yes Yes Double sterile packaging No Yes No Yes Freezer storage system compatible Yes Yes Yes Yes Sterile overwrap bag No Yes No Yes Integral label compartment Yes Yes Yes Yes Complete lot traceability Yes Yes Yes Yes Range of primary bag capacities Yes Yes Yes Yes Table 1: Compatibility of freezing bags with design specifications. Conclusions The CryoMACS Freezing Bag satisfies all of the essential design and handling criteria for GMP processing and clinical cryopreservation of stem cells for transplantation. Based on handling experience and the comparative data from cell cryopreservation efficacy in this pre-clinical study, the CryoMACS Freezing Bag is considered to be suitable for introduction into routine clinical use. 6 CliniMACS Newsletter 1/2009

7 Customer report Bag provider 7AAD viability (%) Viable WBC ( 109/L) CD34 + (%) CD34 + ( 106/L) GM-CFC ( 104/mL) Pre-freeze harvest no BFU-E ( 104/mL) Thaw harvest no. 1 (post freeze) Manufacturer A 1* Manufacturer B 1* Miltenyi Biotec 1* Bag provider 7AAD viability (%) Viable WBC ( 109/L) CD34 + (%) CD34 + ( 106/L) GM-CFC ( 104/mL) Pre-freeze harvest no BFU-E ( 104/mL) Thaw harvest no. 2 (post freeze) Manufacturer A 2* Manufacturer B 2* Miltenyi Biotec 2* Bag provider 7AAD viability (%) Viable WBC ( 109/L) CD34 + (%) CD34 + ( 106/L) GM-CFC ( 104/mL) BFU-E ( 104/mL) Pre-freeze harvest no , ,800 Thaw harvest no. 3 (post freeze) Manufacturer A 3* ,796 89,344 Manufacturer B 3* , ,624 Miltenyi Biotec 3* ,333 90,517 *Average of triplicate experiments Table 2: Viable cell and progenitor counts of three separate CD34-depleted fraction pre-freeze harvests and mean thaw results after frozen storage of the cells in freezing bags from Miltenyi Biotec and two other manufacturers (manufacturer A and B). A) Viable WBC yield after thawing as % of pre-freeze harvest B) Viable GM-CFC yield after thawing as % of pre-freeze harvest C) Thaw BFU-E yield after thawing as % of pre-freeze harvest A1 B1 MB 1 A2 B2 MB 2 A3 B3 MB 3 Cryocontainer Brand 0 A1 B1 MB 1 A2 B2 MB 2 A3 B3 MB 3 Cryocontainer Brand 0 A1 B1 MB 1 A2 B2 MB 2 A3 B3 MB 3 Cryocontainer Brand A = Manufacturer A B = Manufacturer B MB = Miltenyi Biotec CryoMACS Freezing Bag Figure 1 (A C): Thawed viable cell and progenitor yields of three pre-freeze poor CD34 + stem cell harvests using different freezing bags from three manufacturers (mean and SD shown). 7

8 Customer report Isn t it worth two bags? CryoMACS Freezing Bags Exceeds current standards for cryopreservation Single sterile packaging Double assurance with overwrap bag Advanced bag design Miltenyi Biotec Ltd. Almac House, Church Lane Bisley GU24 9DR Surrey UK Phone Fax The CryoMACS Freezing Bags are manufactured by Miltenyi Biotec GmbH and controlled under an ISO certified quality system. 8 CliniMACS These products Newsletter are available 1/2009 in Europe as CE-marked medical devices. FDA 510(k) notification under review with US FDA. MACS and CryoMACS are registered trademarks of Miltenyi Biotec GmbH. Copyright 2009 Miltenyi Biotec. All rights reserved.

9 Products and Customer applications report It is worth two bags! CryoMACS Freezing Bags CryoMACS Freezing Bags are specifically designed for cryopreservation of human blood components allowing freezing, storage, and thawing of human blood components in a clinical setting. Stem cell transplants can be an important part in the therapy for patients suffering from hematopoietic disorders such as leukemia as well as other autoimmune or genetic disorders. Other cell types, like dendritic cells or T cells show great potential in cell-based therapies for a variety of diseases. These cells often need to be stored in liquid nitrogen prior to administration to patients. Miltenyi Biotec s CryoMACS Freezing Bags are specifically designed for cryopreservation of hematopoietic progenitor cells allowing freezing, storage, and thawing of cells. The bags are dedicated for the use in a hospital setting, where medicinal products for patient therapy are manufactured according to GMP. material has been in use for liquid nitrogen preservation for the past 30 years. The bag design is identical for the 250, 500, 750, and 1000 variants of the product, the only difference being the length of the tubing foil cut for welding. The CryoMACS Freezing Bag 50 has a slightly different bag design, where the label pouch can be folded for the bag to fit into small cassettes. Each freezing bag contains an integrated label pouch for placement of the content identification. The bags are also equipped with two eyelets (CryoMACS 50 with one eyelet) to facilitate suspended placement, for example, with infusion rack for administration of the content. The freezing bag is transparent for visual control of the contents. Specific use The CryoMACS Freezing Bags are intended for a single cycle of freezing, storage (down to 196 C), and subsequent thawing (at +37 C) of hematopoietic progenitor cells. This can be heterogeneous hematologic populations (e.g. from cord blood or leukapheresis collections), pluripotent stem cells, or differentiated subpopulations such as antigen-specific and expanded T cells or dendritic cells. Each CryoMACS Freezing Bag consists of one freezing bag with access ports as the primary containment for blood components and one overwrap bag as a secondary containment. The freezing bag and the overwrap bag are placed together into a sterile barrier system, a Tyvek/LDPE pouch, which is again put into a transparent polypropylene bag. Safe and convenient handling The freezing bag is the primary containment for the cryopreservation of human blood components. It consists primarily of a bag welded from a tubular EVA (ethyl vinyl acetate) foil. This durable The bags are fitted with three integrated access points at one end, also made of EVA material. Two access points are designed as identical spike ports for removal and administration of contents with a transfusion set. The spike ports contain a closed twist-off cap and an interior seal, which must be punctured by the transfusion set. The protected spike ports help prevent cross contamination during storage as they cannot be involuntarily disengaged and expose the membrane to the environment. The third access point consists of EVA tubing, connected to a filling assembly. Both the freezing bags and overwrap bags are bags welded from a tubular foil with minimal welds for high durability. The EVA material is identical in 9

10 Products and applications both bags. The freezing bag may be placed into the overwrap bag, which is then heat sealed preferably under vacuum, to remove residual air. The overwrap bag is designed to perform the function of a secondary containment in case that the integrity of the primary containment is compromised. This may aid in providing additional security to the content. To provide standard interfaces for sterile fluid transfer the filling assembly is fitted with an injection port and extension tubing. This again is equipped with two capped female luer lock connectors and a capped male luer lock connector at the respective tubing endings. The tubing (PVC) is suitable for sterile docking with corresponding welding devices (e.g. with the Terumo TSCD ) and each tubing can be closed temporarily with a roller clamp. The freezing bag must be closed by permanent sealing of the EVA tubing and subsequent removal of the filling assembly, which is not intended for frozen storage. The EVA tubing can be utilized to seal off and store separately samples of the content before bag closure. Only those portions of the freezing bag made of EVA are intended for the frozen storage of human blood components. Cycle Mechanical damage Integrity failure Miltenyi Biotec (n=70) * 0 0 * damage occurred in the 8th cycle Manufacturer A (n=20) * 0 * damage occurred in the 3rd cycle Manufacturer B (n=10) * 0 * damage occurred in the 7th cycle Manufacturer C (n=20) * 0 * damage occurred in the 3rd, 4th, and 6th cycle Integrity failure due to misuse Table 1: CryoMACS Freezing Bag 500 and competitor devices: Number of mechanical damages and integrity failures during repeated freeze-thaw cycles. To protect the cells during the freezing procedure, it is necessary to add a cryoprotectant to the media. The most common agent is DMSO in a final concentration of about 10% in the cell suspension. For this purpose the CryoMACS Freezing Bags are suitable for prolonged contact with DMSO and equipped with an injection port, which permits an aseptic processing and provides a DMSO resistant fluid path downstream into the freezing bag. 10 CliniMACS Newsletter 1/2009

11 Products and applications the Cryopreservation of Stem Cell Harvests in Clinical Transplantation) see the customer report section of this newsletter. Cell viability and functionality after freezing Freezing Bag with the overwrap bag and locks Bag integrity after repeated freeze-thaw testing The maintenance of bag integrity over the complete handling process, including filling, sealing, freezing, storage, and thawing is the most important design criterion and performance requirement for the intended use of the CryoMACS Freezing Bags. The results of the repeated freeze-thaw cycles under stringent conditions demonstrated that the design of the CryoMACS Freezing Bags is able to withstand the one freeze-thaw cycle without loss of bag integrity, which is the routine application. Bag integrity is not affected by irradiation, the use of different protective metal cassettes, or the use of cryoprotective agents such as DMSO. CryoMACS Freezing Bags were equivalent or superior to concomitantly tested competitor devices. Clinical application The performance of the CryoMACS Freezing Bags was verified by simulated use in a clinical setting. Performance testing was undertaken by experienced clinicians at the Wolfson Cellular and Gene Therapy Unit, University College London Hospitals (UCLH), under the supervision of the director of the Cellular Therapy Laboratory. This unit performs the cryopreservation of hematopoetic stem cells for therapeutic purposes on a routine basis.¹ For the report (Ings S., Balsa C., Antonio A., and Watts M. (September 2008): Evaluation of CryoMACS Cryocontainer for Performance validation was done with the CD34 + cell poor fraction from routine clinical CD34 + cell purification procedures for therapeutic purposes. This fraction comprises 99% of the cells of a full clinical stem cell harvest from peripheral blood. Three harvests from two healthy donors were used after signed informed consent. CryoMACS Freezing Bags and two predicate devices (from two different manufacturers) were tested in triplicate per harvest. Cells were processed according to institutional protocol, stored frozen at 140 C, delivered in a vapor phase shipper ( 196 C) to a simulated ward, and thawed in a water bath. After complete thawing, blood samples were immediately removed to simulate transfusion to a patient and subjected to the same tests as performed after harvest. The following parameters were measured on both pre-freeze and post-freeze harvests: White blood cell count Viability of CD34 + /45 + cells (7AAD viability marker) in a flow cytometric assay Clonogenicity of GM-CF and BFU-E cells in a 14 day colony assay. The investigators came to the conclusion, that the cell viability and clonogenic activity data are within the range experienced previously in their laboratory and are in agreement with published data from other laboratories. This demonstrates that the design of the CryoMACS Freezing Bags is suitable for the freezing, storage, and thawing of human blood components. Cell viability and functionality data derived from use of the CryoMACS Freezing Bags are equivalent to those of other freezing bags on the market. Based on handling experience and the comparative data from cell cryopreservation efficacy in a the preclinical study, the CryoMACS Freezing Bag is considered to be suitable for introduction into routine clinical use. stated Dr. Mike Watts from the Wolfson Cellular and Gene Therapy Unit, UCLH. 11

12 Products and applications General considerations for clinical use The cell viability depends on several parameters which are not affected by the CryoMACS Freezing Bags, particularly the kind of cryopreservation medium and the freezing and thawing rates. These parameters have to be validated by the clinical user. The instructions for use for the CryoMACS Freezing Bags take this into account: They present warnings and precautions to be observed as well as handling instructions to be followed in order to prevent residual risks arising from inadequate handling. The 510(k) for CryoMACS Freezing Bags is currently undergoing review at the US FDA. Reference 1. Ings, S.J. et al. (2009) ISCT 2009 Annual Meeting Abstracts. Cytotherapy 11 (1): 10. Freezing Bag fits in perfectly into storage cassette. We would greatly appreciate your feedback. Please us at Freezing Bag in an open storage cassette. 12 CliniMACS Newsletter 1/2009

13 Meeting minutes Meeting minutes 2008 /2009 Treg user meeting, ESC 2008, ASH 2008, EBMT 2009, BMT

14 Meeting minutes 1st Treg Network Meeting April 18 to 19, 2008, Noordwhijkerhout, The Netherlands The meeting was intended to provide researchers and clinicians working in the field of Treg cells a platform for extensive discussion and networking. Impact of TA-specific regulatory T cells on spontaneous T cell responses in cancer patients Phillip Beckhove, Germany After depletion of Treg cells it was possible to reactivate these tumor-specific T cells also from PB. Memory tumor-antigen specific effector T cells were found to be enriched in the bone marrow of many cancer patients. Appropriate reactivation of these memory T cells ex vivo with antigen- loaded DCs demonstrated their therapeutic potential after adoptive transfer into mice xenotransplanted with autologous human carcinoma. Autologous CD25-depleted PBMC for adaptive immunotherapy of cancer Daniel Powell, United States The group demonstrated that the peripheral blood (PB) of cancer patients contained high amounts of tumor-specific Treg cells that control the reactivation and proliferation of tumor-specific CD4 and CD8 T cells. After depletion of Treg cells it was possible to reactivate these tumor-specific T cells also from PB. The median progressionfree survival of the treated patients was significantly longer Dr. Daniel Powell reported on their clinical trial with melanoma patients receiving CD25-depleted PBMC after lymphodepletion in combination with high dose IL-2. Monitoring of these patients revealed that the Treg cells vigorously repopulate the peripheral blood of the treated patients (Powell et al., 2007). More recently, patients with low-grade follicular lymphoma received an adoptive immunotherapy using autologous CD25-depleted, ex vivo CD3/ CD28 activated and expanded T cells that were infused four weeks after chemotherapy. The CD4 + T cell numbers increased in all patients by one month. Notably, the frequency and number of circulating CD4 + CD25 + FoxP3 + Treg cells was significantly decreased. The median progressionfree survival of the treated patients was 18 months; significantly longer than the time to progression from last therapy (11 months). 14 CliniMACS Newsletter 1/2009

15 Meeting minutes Developing immunotherapy for cancer Robert Hawkins, United Kingdom Dr. Robert Hawkins gave an overview on his experiences in various clinical studies in the field of Treg depletion in order to augment anti-tumor immune responses. In vitro depletion of CD25 + cells has been undertaken in a clinical trial of renal cell carcinoma with evidence of short-term in vivo changes and some evidence of immune activation (Thistlethwhaite et al., 2007). A phase II study investigating the use of anti-ctla-4 antibody to block Treg cell function in patients with gastric cancer is ongoing. The group is now focusing on the development of genetically engineered T cells to target tumor-associated antigens. In the future a combination of engineered T cells and CD25 + Treg cell depletion could be a promising approach. The group is now focusing on the development of genetically engineered T cells to target tumorassociated antigens. Cord blood transplantation as a model for regulation of GVH reaction Sergio Querol, United Kingdom There is early evidence that suggests a role for Treg cells in the prevention of GVHD. CD25 + FoxP3 + Treg cells represent about 6% of the CD4 population in the peripheral blood of adults and newbornes. Whereas naive Treg cells represents only a small percentage in adulty (<10%) compared to CB (>90%). Dr. Sergio Querol from the Anthony Nolan Cordblood Bank reported on a new concept called CordPharm aiming to produce off-the-shelf products. They are developing a platform for sequential separation of pooled CB units to generate clinical cell products, especially CD133 + and CD25 + cells for tissue regeneration and immunomodulation.... a platform for sequential separation of pooled CB units to generate clinical cell products, especially CD133 + and CD25 + cells for tissue regeneration and immunomodulation. Large-scale selection of natural regulatory T cells for clinical purposes Mauro Di Ianni, Italy Dr. Mauro Di Ianni reported on the implementation of a GMP-conform procedure to enrich CD25 + Treg cells, including a CD8 and CD19 pre-depletion step. In vitro characterization of the enriched Treg cells revealed that the process yielded sufficient Treg cells for potential clinical CD4 + CD25 + regulatory T cells in allogeneic SCT Matthias Edinger, Germany infusion. The group in Perugia is looking for the use of Treg cells in particular in the haploidentical bone marrow transplantation setting, where Treg cells could represent a very potential tool to increase post-transplant immunological reconstitution. Treg cells could represent a very potential tool to increase posttransplant immunological reconstitution. Various mouse models of allogeneic bone marrow transplantation (BMT) demonstrated that transfer of donor CD4 + CD25 + -Treg cells ameliorate or completely prevented GVHD induced by co-transplanted conventional donor T cells. Furthermore, the group from Regensburg demonstrated in a mouse model that CD4 + CD25 + Treg cells did not cause a generalized immune paralysis, thus maintaining the beneficial graft-versus-leukemia effect of donor T cell transfusion. Dr. Matthias Edinger gave an overview about the ongoing first clinical trial on sequential transfusion of donor Treg cells and conventional T cells after allogeneic SCT in patients with AML, CML, and myeloma. At that time, no relapse and no severe adverse effects were observed in all treated patients (n=7). Dr. Edinger s group is working intensively on expansion protocols and phenotyping of expanded Treg cells. They observed that only the naive CD45RA + Treg cell population maintain FoxP3 expression and suppressive activity during an in vitro expansion phase. They conclude that the cytokine pattern and methylation status of a conserved non-coding region of the foxp3 locus of in vitro expanded CD4 + CD25 + Treg cells contribute to a conversion of FoxP3 + to FoxP3 cells. cytokine pattern and methylation status of a conserved non-coding region of the foxp3 locus of in vitro expanded CD4 + CD25 + Treg cells contribute to a conversion of FoxP3 + to FoxP3 cells. 15

16 Meeting minutes Adoptive cell therapy with customized antigen-specific CD4 + CD25 + Tregs Giovanna Lombardi, United Kingdom the group obtained very promising results using Treg cells transduced with retroviral constructs encoding T cell receptors with indirect allospecificity The success of organ transplantation is limited by the immune response to allogeneic tissues and by the morbidity and mortality associated with immunosuppressive drugs that are used to control alloimmunity. Data from rodent models and from monitoring of transplanted patients reveal that one of the keys to achieve and sustain tolerance to an allogeneic transplant is the presence of Treg cells with an indirect allo-specificity for the donor MHC alloantigens. In a rodent model the group demonstrated the possibility to expand Treg cells with indirect allo-specificity ex vivo and their ability to markedly prolong transplant survival following injection in vivo. Furthermore, the group obtained very promising results using Treg cells transduced with retroviral constructs encoding T cell receptors with indirect allo-specificity. By using autologous DCs pulsed with allo-peptides they were able to expand also human allo-antigen specific Treg cells in vitro. In the future, the group is focusing on in vitro expansion protocols to generate sufficient Treg cells for clinical applications. Regulatory macrophages and the pre-operative induction of tolerance Fred Fändrich, Germany pre-operative treatment with donor-derived cells can induce a degree of hyporesponsiveness to donor tissue, which may have facilitated the minimization of pharmacological immunosuppression in these patients. Prof. Fred Fändrich reported on the generation of regulatory macrophages (Mregs) to induce tolerance in transplanted patients. Mregs are a newly characterized, unique subpopulation of human macrophages with T cell regulatory properties. These Mregs are generated in vitro from human monocytes. Notably, the co-culture of Mregs with unactivated CD4 + T cells leads to a relative enrichment of CD4 + CD25 + CD127 low CD45RA + FoxP3 + Treg cells, which appear to arise from a pool of Alloantigen specific Tregs are superior over natural Tregs in inducing and rescuing tolerance after solid organ transplantation Birgit Sawitzki, Germany pre-existing Treg cells. In various transplantation models the group demonstrated that the adoptive transfer of these cells prolonges fully-mismatched solid organ graft survival. Two phase I clinical trials using Mregs have shown that pre-operative treatment with donorderived cells can induce a degree of hyporesponsiveness to donor tissue, which may have facilitated the minimization of pharmacological immuno-suppression in these patients. allo-antigen specific Treg cells were able to induce permanent acceptance of grafts, whereas transfer of natural, unspecific Treg cells only delayed the rejection by several days. Achieving long-term, drug-free graft acceptance is still an unsolved problem in clincial transplantation. The transfer of allo-antigen specific Treg cells could represent an attractive treatment option. The group from Berlin established in the murine system an anti-cd4 mab based protocol for the generation/selection of alloantigen specific Treg cells. They demonstrated in various murine transplantation models that alloantigen specific Treg cells were able to induce permanent acceptance of grafts, whereas transfer of natural, unspecific Treg cells only delayed the rejection by several days. Their data indicate how powerful allo-antigen specific Treg cells are and highlight their therapeutic potential after solid organ transplantation. Human regulatory T cell therapy in the prevention of transplant arteriosclerosis Joanna Wieckiewicz, United Kingdom ex vivo expanded CD4 + CD25 + Treg cells significantly reduced the development of arterioscelorosis in a clinically relevant animal model of vascularized solid organ transplantation in vivo. Transplant arteriosclerosis (TA) is the main cause of chronic allograft loss after cardiac transplantation. The group of Kathrin Wood in Oxford established a clinically relevant humanized mouse model by transplanting human arterial side-branches into the abdominal aorta of immune-deficient mice. With this model they were able to demonstrate for the first time that ex vivo expanded CD4 + CD25 + Treg cells significantly reduced the development of arterioscelorosis in a clinically relevant animal model of vascularized solid organ transplantation in vivo. 16 CliniMACS Newsletter 1/2009

17 Meeting minutes ESC 2008 August 30 to September 3, 2008, Munich, Germany Satellite symposium: Preclinical and clinical aspects of autologous stem cell therapy The four speakers discussed stem cell therapy in cardiovascular patients and presented results of trials and studies using CD133 + cells. Chairs: Jozef Bartunek, Belgium and Karl-Heinz Kuck, Germany. The role of endothelial environment for stem cell homing intravital microscopic analysis following intravascular cell application Alexander Kaminski, Germany Bone marrow stem cells for myocardial regeneration may offer less remodeling and more regeneration. The underlying mechanisms of stem cell migration to non-marrow tissue, however, are yet to be clearly defined in stem cell therapy. Dr. Alexander Kaminski presented results from a study hypothesizing that the local inflammatory response to TNF-α, including endothelial NOS dependant signalling, is required for stromal cell derived factor-1 (SDF-1 α) induced adhesion of c-kit + -bone marrow stem cells to the vascular endothelium. C-kit + stem cell migration was studied in vitro and in vivo. In vitro analysis was carried out via the Boyden chamber. In vivo homing analysis for both c-kit + stem cell and endogenous leukocytes (EL) behavior was done by intravital microscopy of the cremaster muscle microcirculation in wild type and enos knockout mice. C-kit + cell to endothelium interaction was observed exclusively in postcapillary venules. No arterial adherence was observed. The results indicate that TNF-α had a negligible effect on c-kit + cells rolling but SDF-1 α clearly caused the migration of stem cells to non-bone marrow tissue. TNF-α had induced a strong adhesion of EL. After combined treatment with SDF-1 α and TNF-α, endothelial c-kit + cell adhesion rose more than 14-fold while EL behavior remained unchanged. Both NOS inhibition and enos knockout reversed the effect in c-kit + cells but not in EL. Dr. Kaminski concluded that the expression of endothelial NOS is essential for stem cell adhesion and may regulate inflammatory and regenerative tissue response. The augmentation of enos expression may improve stem cell adhesion. TNF-α had a negligible effect on c-kit + cells rolling but SDF-1 α clearly caused the migration of stem cells to non-bone marrow tissue. 17

18 Meeting minutes Intracoronary injection of bone marrow-derived stem cells in patients with large acute myocardial infarction Wolfgang Motz, Germany Twenty of the 28 patients showed functional clinical improvement and at three months follow up, a significant improvement of 6% in ejection fraction was noted in patients treated within one month after MI....results show an increase in clinical functions in nearly all patients. In various clinical trials, it has been shown that intracoronary injection of bone marrow derived stem cells could improve left ventricular function in patients with extended myocardial cell loss after acute myocardial infarction (MI). With strong data from these studies, the Karlsburg Heart and Diabetes Center started cardiac stem cell therapy in patients with large MI. Patients receiving cardiac cell therapy had extended myocardial infarction with decreased left ventricular (LV) function. They also had been pretreated with percutaneous coronary intervention with LV ejection fraction less than 50%. Twenty eight patients between the ages of 38 to 69 years were studied with treatment of CD133 + cells derived from aspirated bone marrow. Intracoronary injections were administered into the vessels supporting the infarcted myocardium. No complications were noted during the stem cell application. The time lag between acute MI and stem cell therapy ranged between <1 month to 96 months. After 3, 12, and 24 months, LV function and clinical status were measured. Twenty of the 28 patients showed functional clinical improvement and at three months follow up, a significant improvement of 6% in ejection fraction was noted in patients treated within one month after MI. No improvements were noted in patients treated more than a month after MI. Based on these observations, Dr. Wolfgang Motz concluded that waiting too long post MI to administer therapy does not improve LV function. At one year follow up, results show an increase in clinical functions in nearly all patients. Ejection fraction improvements were most significant in patients treated within one month of MI. Dr. Motz concluded citing results that indicate stem cell therapy may have more profound effects on vessels beyond just ejection fraction improvements but also at a coronary microcirculation level. TransACT - transplantation of enriched autologous bone marrow-derived CD133 + cells in patients having coronary surgery after STEMI: A double blind placebo controlled trial Raimondo Ascione, UK The use of autologous bone marrow cells paves the future for repairing acute or chronically damaged myocardium. The delivery of CD133 + cells have been shown to be safe from literature and in vitro studies were carried out prior to the design and implementation of the TransACT trials. TransACT 1 is specific to patients after STEMI and TransACT 2 to patients with large end stage ischemic cardiaomyopathy having LV restoration surgery. TransACT 1 is a surgical trial with a rigorous double blind placebo-controlled design. Myocardial infarction was recent with treatment more than ten days and less than three months in 60 patients. Scar transmurality of >50% in at least one segment of LAD is defined by cardiac MRI. The primary outcome is regional left ventricular (LV) thickening and scar transmurality of the injected segments of the LV at six months after surgery. Autologous bone marrow-derived CD133 + cells were used. Selections are done using the CliniMACS Cell Separation System which delivers about 70 to 95% CD133 cells via enrichment as opposed to just 1% within freshly derived mononuclear cells. TransACT 2 essentially works on the same principal of cells derived with injections subendocardially in the transition area. The trial of 40 patients has the same primary outcome as TransACT 1, i.e., regional left ventricular wall thickening. 18 CliniMACS Newsletter 1/2009

19 Meeting minutes Enhanced functional response of CD133 + circulating progenitor cells in patients following acute myocardial infarction Johannes Waltenberger, The Netherlands Endothelial cells and endothelial precursors express VEGF receptors and are both involved in regenerative processes in angiogenesis and arteriogenesis. Vascular repair and growth are dependent on endothelial cells while monocytes express VEGF receptors as well. Endothelial cells are difficult to harvest and hence monocytes provided an ability to study VEGF receptors. Reduced monocyte chemotaxis was noted in the presence of cardiovascular risk factors. The hypothesis was that the reactive oxygen species (ROS) of monocytes were responsible for this. CD133 + cells meanwhile show a ROS-resistant ability. These circulating progenitor cells (PCs) contribute to cardiac recovery following myocardial infarction. The functional chemotactic response of PC to VEGF in patients early after myocardial ischemia was investigated. The number and phenotype of PCs were characterized using flow cytometry. The chemotactic response towards members of the VEGF family was categorized and analyzed. The CD133 + PC number was significantly 2-fold higher in AMI patients compared to coronary artery disease (CAD) patients and control (CTR), while CAD was not different from CTR. The chemotactic response of CD PCs to VEGF-A, PIGF-1, and VEGF-E was significantly enhanced in AMI patients compared to CAD patients. Dr. Waltenberger concluded that in coronary artery disease with chronic inflammation, there is minimal dysfunction of CD133 + which gives them the ability to play a regenerative role if required. In AMI with acute inflammation there is an enhanced function of CD133 + which makes them a likely candidate for repair. The enhanced chemotactic response of CD133 + cells following myocardial infarction represents a novel principle potentially important in early cardiovascular repair. The Satellite Symposium Preclinical and clinical aspects of autologous stem cell therapy at the European Society of Cardiology Congress 2008 was supported by an educational grant from Miltenyi Biotec. An abstract booklet and DVD with all presentations of this symposium has been prepared. Please refer to page 31 to request a copy....that in coronary artery disease with chronic inflammation, there is minimal dysfunction of CD133 + which gives them the ability to play a regenerative role if required. The CD133 + PC number was significantly 2-fold higher in AMI compared to CAD and CTR... 19

20 Meeting minutes 50th Annual Meeting of the American Society of Hematology December 5, 2008, San Francisco, California, USA Satellite symposium: Cellular therapy stem cell transplantation from matched related and unrelated donors Chair: Richard J. O Reilly, USA The speakers presented the development and current status of T cell-depleted stem cell transplantation as well as results from pilot studies investigating specific T cell fractions and NK cells for immunotherapy. Introduction Richard J. O`Reilly, USA Dr. Richard J. O`Reilly reviewed the biology and therapeutic potential of T cell depleted HLAmatched and disparate marrow and peripheral blood stem cell transplants. In 1977, he demonstrated that HLA-compatible transplants from unrelated donors could be used to correct a lethal blood disorder. HLA haplotype disparate parental transplants adequately depleted of T cells could be used to engraft and reconstitute both hematopoiesis and immunity in patients with SCID or leukemia with a low risk of either acute or chronic graft versus host disease (GvHD). The development of technical options for T cell depletion (TCD) and donor lymphocyte infusion (DLI) tailoring during the recent years serves as an efficient basis for transplantation protocol optimization. 20 CliniMACS Newsletter 1/2009

21 Meeting minutes T cell depleted transplants for acute leukemias Richard J. O Reilly, USA In the 1980s, the group demonstrated that HLAA, -B, -DR haplotype disparate parental bone marrow transplants (BMT) depleted of T cells by soybean agglutination and E-rosette depletion (SBA-E- BMT) could durably engraft and reconstitute hematopoiesis and immunity in children with SCID without causing acute or chronic GvHD. Thereafter, SBA-E-BMT from HLA-matched and disparate donors was administered to treat adults and children with ALL, AML, MDS, or CML without post-transplant immunosuppression to prevent GvHD. While the incidences of both grade II IV GvHD and chronic GvHD were consistently low, the incidence of graft failures was unacceptably high. Modification of the cytoreductive regimens resulted in a more efficient depletion of reemergence of radioresistant host T cells post transplant, which exhibited alloantigenspecific cytotoxic or cytoinhibitory activity against donor hematopoietic cells. Graft rejections were eliminated and late graft failure rates were reduced to <5%. Recent trials base on this improved cytoreductive regimen, using either SBA-E-BMT or G-CSF mobilized PBSC grafts depleted of T cells by initial positive selection of CD34 + cells by immunoadsorption followed by E-rosette depletion (CD34 + E-PBSC). Single-center experience indicates that the allogeneic CD34 + -based approach performed after myeloablative conditioning, but without post transplant immunosuppression is associated with consistent engraftment and low incidences of acute and chronic GvHD. For patients transplanted in early remission of acute leukemia, DFS rates are 70%, with low rates of relapses in recipients of both matched related and unrelated transplants. For patients transplanted in early remission of acute leukemia, DFS rates are 70%, with low rates of relapses Impact of CD8 depleted donor lymphocyte infusions on immune reconstitution after T cell depleted matched allogeneic stem cell transplantation Ralf G. Meyer, Germany The combination of fludarabine/melphalanbased reduced-intensity allo-transplantation with in vivo TCD by the anti-cd52 antibody alemtuzumab has demonstrated efficient engraftment and reduced GvHD. However, it is associated with a slow lymphocyte recovery and thereby reduced anti-infectious and anti-tumor immunity. In order to improve immune reconstitution after this protocol, Dr. Ralf G. Meyer investigated the early prophylactic use of CD8 depleted DLI. Therefore, the GMP compliant CliniMACS CD8 depletion procedure was used, allowing efficient CD8 + cell depletion (2.5 to 4 logs) from leukaphereses, while NK cells, B cells, and CD4 T lymphocytes remained in the cellular product. DLI were infused in increasing doses in the absence of immunosuppressive medication and clinical signs of GvHD. Seven out of 24 patients developed acute GvHD of grade 2 to 4 (29%) following CD8 depleted DLI. Two of these patients progressed to extensive chronic GvHD. After CD8 depleted DLI, transferred T cells proliferated in vivo and promoted CD4- and CD8-mediated antiviral responses against cytomegalovirus. In the treated cohort, the majority of patients who qualified for prophylactic DLI showed late (more than day +90) mixed chimerism, mainly in the T cell lineage. The application of CD8 depleted DLI was efficient in all of these patients to restore full donor chimerism. The resulting DLI (i) retain the capability to support antiviral, but also alloreactive T cell reconstitution, (ii) revert a late mixed chimerism to full donor, and (iii) may also mediate a graft-versusmalignancy effect. As the rate of GvHD after CD8 depleted DLI appears to be lower, their application in a preemptive or prophylactic setting might be favourable compared to the use of unmanipulated DLI. application in a preemptive or prophylactic setting might be favourable compared to the use of unmanipulated DLI. 21

22 Meeting minutes Novel uses of umbilical cord blood for NK cell and regulatory T cell therapy Jeffrey S. Miller, USA Treg cell subsets from adult and UCB may exhibit beneficial effects with regard to engraftment success and GvHD control. Co-operation between both the innate and adaptive arms of the immune system is required to safely induce immune reconstitution after allogeneic transplantation that protects against infection and relapse but without intolerable GvHD. Dr. Jeffrey S. Miller reflects the current status of clinical NK cell research. New insights into the physiology of NK cells point towards a highly complex mechanism of activation, dependent on the co-expression of markers of activation and inhibition on the NK cell surface beyond KIR expression pattern. From human clinical trials, it has been increasingly clear that NK cells and T cells compete for the same factors, and early NK cell responses may be best realized in a setting where T cell depletion is performed. Currently, studies are ongoing to evaluate if CD34- selected KIR ligand mismatched grafts will lead to better disease free survival. However, growing evidence suggests that NK cells reconstituting from stem cells early after transplant may not be fully functional and mature NK cells with further activation may be more optimal. While some laboratories have focused on ex vivo expansion to activate and expand adult NK cells, Dr. Miller s group hypothesizes that in vivo expansion may be more physiologic in the setting of a lymphodepleting regimen for AML patients. Study results show that adoptive transfer of haploidentical peripheral blood (PB)-derived NK cells (CliniMACS CD3-depleted lymphapheresis products) without transplantation in 32 patients resulted in ten patients achieving a complete remission (CR). However, long-term follow-up advises further therapy optimization. Concept of the current platforms is to combine haploidentical NK cells and hematopoeitic cell transplantation in one procedure. Two strategies were developed, a myeloablative one using NK cells and stem cells derived from clinical umbilical cord blood (UCB) units, and a nonmyeloablative one using mature NK cells and CD34-selected haploidentical NK cells from the same donor. Dr. Miller and colleagues observed an enhanced tendency of in vivo NK cell expansion 14 days after cell infusion as a consequence of TBI in combination with Flu/cyclophosphamide compared to non-tbi containing chemotherapy. Furthermore, mature NK cells from peripheral harvests expanded better than from UCB. However, despite achieving remissions these transplantation platforms require further therapeutic optimization due to improvable long term clinical success. Lastly, Treg cell subsets from adult and UCB may exhibit beneficial effects with regard to engraftment success and GvHD control. Thus, understanding of various options for treatment protocol manipulation will allow for improvement of desired therapeutic effects. Donor-type CD4 + CD25 + regulatory T cells in HLA-matched allogeneic SCT Matthias Edinger, Germany Treg cells can be enriched under GMP conditions and in vitro expanded Treg cells do survive after adoptive transfer. Dr. Matthias Edinger emphasized the vital function of CD4 + CD25 + Treg cells in induction and maintenance of peripheral self-tolerance. The ability of Treg cells to suppress allo-responses in vitro prompted several groups to investigate their role in BMT. The common goal of those studies was to confirm findings in the mouse system with regard to induction of tolerance to allo-antigens and thereby preventing GvHD. Furthermore, it was shown that murine donor Treg cell infusion does not cause generalized immune paralysis, thus maintaining the beneficial graft-versus-leukemia (GvL) effect of donor T cell transfusions. Dr. Edinger presented preliminary safety and feasibility data on the administration of donor Treg cell products to patients after HLA-matched SCT in a DLI setting. For future applications, methods for their in vitro expansion and the impact of various isolation strategies (CD127 versus CD45RA + Treg) on the purity and functional characteristics of Treg cell products were discussed. He concluded by saying that Treg cells can be enriched under GMP conditions and in vitro expanded Treg cells do survive after adoptive transfer. Combined steroid/mmf treatment does not preferentially affect Treg cells. 22 CliniMACS Newsletter 1/2009

23 Meeting minutes Adoptive T cell transfer for the treatment of CMV, ADV, and EBV infections post allogeneic stem cell transplantation Tobias Feuchtinger, Germany Allogeneic stem cell transplantation (SCT) can expose patients to a transient but marked immunosuppression, during which viral infections are an important cause of morbidity and mortality. In fact, endogenous reactivation of persistent viruses is frequent, like Cytomegalovirus (CMV), Adenovirus (ADV), and Epstein-Barr-virus (EBV). Dr. Tobias Feuchtinger described the manufacturing of Ag-specific CD4 + and CD8 + donor T cells based on IFN-γ secretion using the CliniMACS Cytokine Capture System. For T cell stimulation immunodominant complete viral proteins, namely hexon protein (ADV), pp65 (CMV) and EBNA1, or LMP2 (EBV) were used to enable the application in all possible HLA environments. Adoptive T cell transfer has been applied to children and adults with increased viral load under standard antiviral chemotherapy after allogeneic SCT from matched unrelated or haploidentical donors as a second line treatment. A successful induction of an antiviral immunity was possible in the majority of cases, leading to a significant reduction of the viral load or clearance of the infection, pointing towards a successful in vivo expansion of virus-specific T cells. Neither acute side effects nor relevant GvHD induction have been seen after adoptive T cell transfer. Dr. Feuchtinger emphasizes that adoptive transfer of specific T cell immunity is safe and feasible and may protect from virus-related complications after allogenic SCT. The Friday Satellite Symposium, supported by an educational grant from Miltenyi Biotec preceded the 50th Annual Meeting of the Annual Society of Hematology. Dr. Feuchtinger emphasizes that adoptive transfer of specific T cell immunity is safe and feasible and may protect from virus-related complications after allogenic SCT. 23

24 Meeting minutes EBMT March 29 to April 1, 2009, Göteborg, Sweden Satellite symposium: Cellular therapies therapeutic options for stem cell transplantation The satellite symposia discussed technical aspects of CliniMACS T cell depletion and innovative immunotherapy approaches using NK cells, regulatory T cells, and antigen-specific T cells. Rapid and effective large-scale CD3 T cell depletion using the CliniMACS System Josefina H. Dykes, Sweden Depletion 3.1 was superior to Depletion 2.1 for both CD34 + cells (90% versus 80%, p<0.05) and CD3 - cells.. The Depletion 3.1 program offers a large-scale, time-saving method for direct T cell depletion with excellent CD34 + cell recovery, as reported by researchers working on CD3 T cell depletion using the CliniMACS System. The addition of a blocking reagent causes an efficient reduction of T cell numbers. Efficient T cell depletion in the stem cell graft is a prerequisite in haploidentical transplantations. The team investigated the performance of two CliniMACS Programs for direct T cell depletion, the Depletion 2.1 program and the novel Depletion 3.1 program. The researchers aimed to provide the best possible peripheral blood progenitor cells graft suitable for haploidentical transplantation in children and adults. The median log 10 T cell depletion rate was significantly better with the Depletion 2.1 compared to the Depletion 3.1 (log 3.6 versus log 2.3, p<0.05). The introduction of the use of immuneglobulin (IgG) prior to anti-cd3 MicroBeads incubation for non-specific binding significantly improved the performance of both the depletion programs (log 4.5 versus log 3.3, p<0.05). With regards to the median recovery, Depletion 3.1 was superior to Depletion 2.1 for both CD34 + cells (90% versus 80%, p<0.05) and CD3 cells (87% versus 75%, p<0.05). The median processing time was shorter with Depletion 3.1 (0.35 hr./10 10 total cells versus 0.9 hr.). Rapid engraftment was achieved in all but one patient (n=17) and the incidence of acute GvHD was less than 10% (grade l/ll) and 0% (grade III/lV). 24 CliniMACS Newsletter 1/2009

25 Meeting minutes Haploidentical HSCT in patients with high-risk acute leukemia Franco Aversa, Italy Haploidentical transplant provides an alternative approach for patients with high-risk acute leukemia, particularly those who urgently need transplantation, report researchers. The haplo transplant setting provides prompt availability of the same donor for the few patients who reject the graft or who relapse, and secondly the marked benefits of an NK cell alloreactive donor in AML patients. The CliniMACS Instrument was used to positively select CD34 cells. The results found leukemia relapse was lower than expected in patients who were high risk and did not benefit from a GvHDrelated GVL effect. Unlike matched transplants, haploidentical transplants can rely on another type of NK cell mediated alloreactivity. Prof. Aversa also presented evidence showing that haploidentical SCT is improved by using the mother as a donor. High engraftment rate, no GvHD and excellent quality of life in high-risk acute leukemia patients transplanted in remission were noted. Cell-mediated killing of leukemia and neuroblastoma using natural killer cells after haploidentical stem cell transplantation Ulrike Köhl, Germany haploidentical SCT is improved by using the mother as a donor. High engraftment rate, no GvHD, and excellent quality of life in high-risk acute leukemia patients transplanted in remission Highly purified NK cells without or with further activation to increase cytotoxicity may be infused in recipients of haploidentical stem cell transplantation (HSCT), report researchers. As adoptive immunotherapy with unmodified donor lymphocyte infusions after HSCT is associated with a high risk of severe graft versus host disease (GvHD), treatment with highly purified NK cells could provide an alternative option since NK cells might not mediate GvHD development. A prospective phase ll study was conducted on the pre-emptive use of freshly isolated or IL-2 stimulated NK cells, respectively. In this study, high-risk patients with malignant diseases lacking an HLA identical family donor received immunotherapy with either freshly isolated or IL-2 stimulated NK cells (NK-DLI) post haploidentical stem cell transplantation. Initial data showed that NK cell purification and expansion is feasible and that unstimulated as well as IL-2 stimulated NK-DLIs are well tolerated. In compliance with certain limits of residual CD3 + numbers, no GVHD occurred. No enhanced immune reconstitution following NK-DLI was seen; instead infusion of activated NK cells induced a decrease of PB NK cells, APC, and eosinophils. Furthermore, an enhanced cytotoxicity of IL-2 stimulated NK cells was seen in vitro. No enhanced immune reconstitution following NK-DLI was seen; instead infusion of activated NK cells induced a decrease of PB NK cells, APC, and eosinophils. Therapeutic potential of large-scale separated CD4 + and CD25 + regulatory T cells Bruce R. Blazar, USA Phase I trials of umbilical cord blood (UCB) and peripheral blood (PB) Tregs given at the time of allogeneic hematopoietic cell transplantation are in progress and will provide needed toxicity data in humans. So far rodent studies have demonstrated a marked effect of ex vivo expanded Tregs on inhibiting graft-versus-host disease (GvHD) and host T cell mediated bone marrow graft rejection. Both human UCB and peripheral blood (PB) Tregs have been produced using antibody-coated magnetic bead-based isolation and expanded with anti-cd3/cd28-mab coated microspheres. In pre-clinical studies the in vitro costimulatory requirements and in vivo biological efficacy of both human Treg populations were explored. For Tregs isolated from PB, CD28, but not OX40 or 4-1BB costimulation, maintained high levels of Foxp3 expression and in vitro suppressive function. Adding rapamycin was required to expand Tregs from PB that are capable of inhibiting GvHD in a mouse model. Whereas, adding rapamycin to UCB Tregs reduced expansion and suppressive function. 25

26 Meeting minutes... non-cell sorter, antibodycoated MicroBead approach can be used to isolate UCB and PB Tregs. Large numbers ( ) of adult PB Tregs can be produced by negative and positive selection using GMP magnetic beads followed by a single day stimulation using anti-cd3/28-mab beads with IL-2 + rapamycin under large-scale, cgmp conditions. UCB Tregs can be purified by positive selection using GMP magnetic beads and expanded ~600 fold with CD3/28 MicroBeads + IL2 alone. OX40L and 4-1BBL costimulation increased Treg expansion with retention of MLR suppression for UCB but not for peripheral blood Tregs. Increased survival of Tregs in vitro and in vivo correlates with GVHD inhibition. In summary a non-cell sorter, antibody-coated MicroBead approach can be used to isolate UCB and PB Tregs that can be expanded to large numbers of Tregs while retaining their potent in vivo capacity to inhibit xenogeneic GvHD. Adoptive T cell immunotherapy for cytomegalovirus Karl S. Peggs, UK Infusion of cytomegalovirus (CMV)-specific T cells leads to reduction of viral reactivation in patients after allogeneic stem cell transplantion who are immunosuppressed. Infusion of cytomegalovirus (CMV)-specific T cells leads to reduction of viral reactivation in patients after allogeneic stem cell transplantion who are immunosuppressed. Current strategies allow direct isolation of CMV-specific T cells from donor apheresis products, based on the relatively high frequencies of CMV-specific T cells in healthy CMV-experienced donors. One of the approaches is to perform an overnight re-stimulation of donor peripheral blood mononuclear cells with rcmv-pp65 protein followed by selection based upon interferon-γ secretion using CliniMACS Cytokine Capture System (IFN-γ) and CliniMACS technology. Cells were infused either pre-emptively following detection of CMV by PCR surveillance or prophylactically at day 40 to 50 post transplant. Following infusion, in vivo expansion of the cells were seen in all patients, including those in whom no subsequent viral DNAemia was detected. GVHD incidence appeared no higher than in comparable patients not receiving cellular therapy. These data have initiated a larger randomized comparative study (CMV-IMPACT) which has commenced across eleven UK transplant centers. The study aims to establish the efficacy of CMV-specific cellular therapy on an intend-to-treat basis. 26 CliniMACS Newsletter 1/2009

27 Meeting minutes BMT Tandem Meetings February 11 to 15, 2009, Tampa, Florida, USA Here are some highlights from the BMT Tandem Meetings organized by the American Society of Blood and Marrow Transplantation and the Center for International Blood and Transplant Research. In general, some of the topics discussed were: stem cell mobilization, treatment of related complications like viral- and fungal infections, treatment options for GvHD, the role of NKT cells in promoting graft acceptance, and cord blood approaches. All oral presentation and poster abstracts are available on the website: Session: Regulation of alloresponses Mathias Edinger, Germany Adoptive transfer of regulatory T cells for GvHD prophylaxis The first phase I trial: to date 9 Pts treated with Treg DLI after SCT: no adverse events (e.g. GvHD, infections) (CliniMACS System). Compassionate use: treatment of one Pts with GvHD grade IV expanded naive Tregs. All clinical signs of GvHD were cleared. Combined MMF and CsA treatment did not affect Treg population in vivo. Session: Pediatric disorders, histocompatibility/alternative stem cell sources, solid tumors, stem cell biology, and supportive care Vita Salsman, USA Adoptive transfer of Her-2 specific T cells eradicates experimental glioblastoma multiforme. T cells retrovirally transduced with Her2-specific/CD28 CARs (chimeric antigen receptor), kill autologous GBM cells (mouse model). 27

28 Meeting minutes Session: Pediatric disorders, histocompatibility/alternative stem cell sources, solid tumors, stem cell biology, and supportive care Elizabeth Shpall, USA Depletion of CD3 and/or CD14 cells from cord blood improves ex vivo expansion of stem cells in Texas Cord Blood Bank. MD Anderson MSC-CB expansion trial: Coculture of stem cells with mesenchymal stem cells (MSC) mimicking a stem cell niche Clinical depletion of CD3/CD14 increased fold expansion. Expanded grafts do not induce long-term engraftment, this is induced by an umanipulated graft given later. Session: Immune reconstitution, autologous tx, and graft processing Ulrike Gerdermann, Germany CSA (MACS Cytokine Secretion System; CCS (CliniMACS Cytokine Capture System)). Multivirus-specific T cell immunotherapy to prevent or treat infections. Reactivation of multispecific T cells by transfected DC s (nucleofection). Pooling of transfected DC s (different specificities) leads to the generation of multispecific T cell lines without observing antigenic competition. Selection of INF-γ secreting T cells 24 hours post DC stimulation by CSA (MACS Cytokine Secretion System; CCS (CliniMACS Cytokine Capture System)). Total procedure can be performed in less than 10 days. Session: Lymphoma/multiple myeloma Catherine Bollard, USA Complete tumor response in lymphoma patients who receive autologous T lymphocytes. LMP-CTL: EBV transformed LCLs transduced with LMP1 or LMP2 (Ad5f35 vector). 14 patients adjuvant: 12 remain in remission, one relapse, one too early. 12 patients relapsed disease: 80% response rate. Session: Pediatric disorders Yoonsun Choi, USA High throughput non-viral gene transfer of T cells New platform technique for gene transfer (CAR technology). Cost effective approach to genetic transfer of large numbers of minimally manipulated cells. Expression of CAR transgene: 80% 24 hours post electroporation, expression is transient, could be overcome by repeated infusions. 28 CliniMACS Newsletter 1/2009

29 29

30 FAQs Frequently asked questions Do I have to always use the overwrap bag when freezing cells in the CryoMACS Freezing Bag? No, you can use the CryoMACS Freezing Bag without the overwrap bag. The overwrap bag provides potential extra security. It protects both the freezing bag and the stored blood product. It helps to maintain the sterility of the freezing bag and helps to prevent the risk of cross-contamination during cryopreservation. Are CryoMACS Freezing Bags secured against nitrogen ingress into spike ports during cryoperservation? Yes, the CryoMACS Bags have two spike ports, secured with sealed twist off protective caps. Is it possible to use the EVA tubing for taking quality control samples? Yes, the extra long EVA tubing is suitable for storage in nitrogen and especially designed for drawing quality control samples out of heat-sealed tube sections. Are there special accessories needed for transferring the cryoprotectant or the blood product into the CryoMACS Freezing Bag? No, the CryoMACS Freezing Bag filling assembly is equipped with all standard connection ports (Luer lock female/male; injection port). Furthermore the PVC tubing of the filling assembly is suitable for sterile docking (e.g. with Terumo Sterile Docking Device). The CryoMACS Freezing Bag can therefore easily be introduced into your routine working procedures. When using the overwrap bag do I need to use larger storage cassettes? No, the filled freezing bag with its corresponding overwrap bag fits into the corresponding storage cassettes. There is no need to use larger storage cassettes. How fit are CryoMACS Freezing Bags for a sterile workflow in clean rooms? CryoMACS Freezing Bags fit very well with a sterile workflow. Each CryoMACS Freezing bag with its corresponding overwrap bag is individually packed and sterilized by electronbeam irradiation. An additional outer packaging can be disinfected and makes clean room handling easy. 30 CliniMACS Newsletter 1/2009

31 Calendar, fax reply form Conference calendar 2009/2010 meet us at the booth! Date Congress Webpage December 5 to 8, 2009 ASH 51st Annual Meeting, New Orleans February 4 to 7, th International Conference on New Trends in Immunosuppression and Immunotherapy, Geneva March 21 to 24, 2010 EBMT, Vienna March 27 to 28, 2010 GVH and GVL Reactions 2010, Regensburg April 20 to 24, 2010 NK 2010, Dubrovnik nkdubrovnik.com May 23 to 26, th ISCT Meeting, Philadelphia Meeting Fax reply form CliniMACS Newsletter Vol. 9 No. 1/2009 Please mark below and fax to: Miltenyi Biotec, Marketing Department, Attn.: Brigitte Borchert Fax no Treg Network Meeting EBMT BMT Tandem Meetings Abstract booklet, Miltenyi Biotec symposium Regulatory T cell Network Meeting Abstract booklet, Miltenyi Biotec symposium Cellular therapies: therapeutic options for stem cell transplantation Abstract booklet, Miltenyi Biotec symposium Emerging applications for cellular therapy ESC Meeting (booklet) (DVD) ASH Meeting Clinical Product Catalog 2009/ CryoMACS Freezing Bags Abstract booklet and DVD with all presentations, Miltenyi Biotec symposium Preclinical and clinical aspects of autologous stem cell therapy Abstract booklet, Miltenyi Biotec symposium Cellular therapy: Stem cell transplantation from matched related and unrelated donors Product information Please check the box if you wish to receive further information. Your local Miltenyi Biotec representative is available to visit your site and discuss our products in more detail. My research focus is Surname, First name Institute, Department Street City/Postal code/country Phone Fax 31

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