1 Current Opinion in Pediatrics Cord Blood Banking and Transplantation: Advances and Controversies --Manuscript Draft-- Manuscript Number: Full Title: Article Type: Corresponding Author: Cord Blood Banking and Transplantation: Advances and Controversies Review Article Mervin C Yoder Indianapolis, IN UNITED STATES Corresponding Author Secondary Information: Corresponding Author's Institution: Corresponding Author's Secondary Institution: First Author: Mervin C Yoder First Author Secondary Information: Order of Authors: Mervin C Yoder Order of Authors Secondary Information: Powered by Editorial Manager and ProduXion Manager from Aries Systems Corporation
2 *Manuscript Cord Blood Banking and Transplantation: Advances and Controversies Mervin C. Yoder, MD Distinguished Professor and Richard and Pauline Klingler Professor of Pediatrics Department of Pediatrics Indiana University School of Medicine Indianapolis, IN Phone:
3 Abstract Purpose of review: A review of papers published since January 2012 on the topic of cord blood banking and cord blood stem cell transplantation was conducted for this the 25 th anniversary year of the first cord blood transplant performed in a human subject. Recent findings: Cord blood banking is performed throughout the world. Umbilical cord blood (UCB) transplantation is recognized as an acceptable alternative stem cell source for pediatric and adult subjects requiring a hematopoietic transplant, particularly for patients of racial and ethnic minorities. To further advance the use of UCB, methods to enhance UCB stem cell expansion, engraftment, and maintenance may be required. Controversy on the most effective and economically sustainable model for banking and storing an optimal UCB product continues to persist. Summary: Cord blood banking and transplantation of cord blood stem cells has advanced rapidly over the initial 25 years as more than 30,000 patients have benefited from the therapy. New concepts on the use of methods to expand UCB stem cells for transplantation and use for non-hematopoietic indications may increase demand for UCB over the next few decades. Keywords: Umbilical cord blood Umbilical cord blood banking Cord blood stem cell transplantation
4 Introduction This has been a notable year for cord blood transplantation and banking, since it was 25 years ago that a child with Fanconi Anemia received an umbilical cord blood (UCB) transplant. Since that time, more than 600,000 UCB units have been cryopreserved and stored in banks throughout the world and >30,000 transplants have been performed using stored material . We will briefly point out some notable achievements that have occurred over the past 25 years and highlight some recent advances in cord blood transplantation. We will also point out a few areas where UCB has been proposed as a novel source of stem cells that may provide repair or regeneration of tissue function in non-hematopoietic systems. Finally, we will discuss the ongoing challenge of providing education to the public as to the different types of cord blood banks that collect and preserve UCB under different economic and blood banking standards. Overview of highlights from the first 25 years of cord blood transplantation and banking The first UCB transplant was successfully performed through the efforts of a team of international investigators . A child with FA who was suffering from severe aplastic anemia was deemed a potentially suitable candidate when a tissue matched sibling was born and UCB was isolated and cryopreserved in the laboratory of Dr. Hal Broxmeyer. Dr. Arleen Auerbach determined that the UCB of the donor sibling was unaffected by FA. Dr. Eliane Gluckman had previously developed pre-transplant conditioning regimens for patients with FA, and successfully performed the UCB transplant in October of 1988 after appropriate ethics review [1, 2]. The patient displayed signs of donor cell engraftment on day 22 post-transplant and subsequently achieved a full hematopoietic reconstitution with donor cells. Now 25 years later, this healthy patient continues to show complete hematologic and immunologic donor cell chimerism . Several years after this epic event, the first public UCB bank was formed at the New York Blood Center  and in 1993 the first unrelated UCB transplant was performed [4, 5].
5 Subsequently UCB was increasingly utilized in pediatric patients. When comparing bone marrow versus UCB as a source of matched sibling donor stem cells`, transplantation of UCB was associated with delayed neutrophil and platelet time to engraftment`, reduced acute and chronic GVHD`, but similar survival . In a recent analysis of 5 year outcomes of children with acute leukemia that received a sibling UCB transplant, the probability of disease free survival (DFS) was 44% . In children with acute leukemia that received either an unrelated matched UCB or an unrelated matched bone marrow transplant, recipients of the UCB had better outcomes . An increase in transplant related mortality (TRM) was detected in children receiving < 3 X 10 7 total nucleated cells per kilogram bodyweight and a 1 HLA-disparate match or in children given a 2 HLA-disparate UCB transplant, pointing out the importance of UCB unit selection for improving outcomes . One approach to enhancing cell dose is to provide a double UCB transplant. A preliminary analysis of a clinical study directly comparing the use of a single versus a double UCB transplant in pediatric patients with a hematologic malignancy did not show a survival advantage [1, 9]. Use of UCB as a stem cell source in adult patients with leukemia failed to result in the promising results obtained in pediatric patients with concerns that the neutrophil and platelet recovery times were significantly delayed and there was high TRM . However, improvements in patient selection, better supportive care, and the use of higher infused cell dose have been associated with increased survival. A recent analysis of factors that affect mortality following myeloablative UCB transplantation in adult subjects identified older age, advanced disease, and limited center experience correlated with worse survival . However, a remarkable 60-70% 5 year DFS was reported by one group from Japan for adult patients with acute myelogenous leukemia (AML) that underwent myeloablative conditioning prior to receiving a single UCB transplant . To improve outcomes in the United States, combining reduced intensity conditioning with double cord blood transplantation has resulted in 30-50% DFS in adult subjects with malignancy [13, 14]. Improvements in UCB unit selection are expected to
6 further enhance outcomes in adult subjects that need an UCB transplant . Thus, one recent review recommends that UCB transplantation should be considered in all high-risk adult subjects with AML in whom an allogeneic stem cell transplant is indicated but who lack a matched related or unrelated donor . Methods to expand UCB hematopoietic stem cells Given the delayed donor cell reconstitution of UCB recipients and the associated increased incidence of late viral infections and other TRM , strategies to enhance the numbers of transplanted stem cells in each UCB unit have long been desired [17, 18]. Results from recent clinical trials testing the safety and feasibility of expanding an UCB unit ex vivo and then infusing with a second unmanipulated UCB unit have been reported. Notch-mediated expansion of UCB capable of rapid myeloid reconstitution Activation of endogenous Notch receptors on UCB CD34 + cells via co-culture on immobilized engineered Delta-like ligand 1 was known to increase the CD34 + content nearly 100-fold and to increase the engraftment of the Notch activated cells in immunodeficient mice . In preliminary clinical studies, use of the same approach provided a significant expansion of UCB CD34 + cells and when co-infused with an unmanipulated UCB unit, reduced the time to an absolute neutrophil count (ANC) >500 cells per L to a median of 16 days. This time was significantly reduced compared to a median of 26 days for ANC recovery in patients concurrently treated at the same institution with a double UCB transplant . A recent update to that report indicates that 17 patients have now been enrolled and the median time to ANC recovery has been shortened to 11 days compared to 25 days in a concurrently enrolled institutional cohort of 36 patients undergoing a double UCB transplant . Since the expanded unit predominated during the first week post-transplant, evidence exists that the Notch activated UCB cells provide rapid myeloid recovery.
7 UCB engraftment with ex vivo mesenchymal-cell co-culture Expansion of hematopoietic progenitor cells in unfractionated UCB cells has been known to be markedly enhanced upon co-culture with mesenchymal stromal cells . In a recent report, 31 adult subjects with hematological cancer that received an UCB transplant with 1 expanded unit and 1 unmanipulated unit were compared to 80 historical control subjects who received 2 unmanipulated UCB units. The median time to neutrophil engraftment was 15 days in the patients that received the expanded unit plus the unmanipulated unit compared to 24 days in the control patients that received a double UCB unit transplant; a significant improvement . The median time to platelet recovery was also significantly shortened from 49 days in the control patients to 42 days in the patients receiving the expanded plus unmanipulated UCB. Of interest, the dose of the CD34 + cells and total nucleated cells per kilogram bodyweight in the recipients of the expanded unit significantly correlated with the time to neutrophil recovery. Long-term engraftment of more than 1 year was produced primarily by the unit of unmanipulated UCB in these patients. These results support the hypothesis that transplantation of UCB cells expanded with mesenchymal cells shortens the time to neutrophil and platelet recovery in adult subjects . Other approaches to expand UCB A variety of other approaches have been examined for expanding human UCB cells. One approach expands a portion of an UCB unit using selected growth factors in the presence of a copper chelating agent tetraethylpentamine and this strategy appeared to enhance single UCB engraftment in a phase I/II clinical trial . A number of preclinical studies have provided promising pathways to expand UCB. A purine molecule name StemRegenin1 (SR1) was identified in an unbiased screen of 100,000 compounds to expand CD34 + cells. UCB cells treated with SR1 demonstrated a 50-fold increase in CD34 + cells and a 17-fold increase in UCB cells that repopulate immunodeficient mice and may be one promising agent to expand UCB . In another approach, human umbilical vein endothelial cells (HUVECs) were infected with a
8 lentivirus encoding the E4ORF1 gene of adenoviruses to permit long term culture and survival of the infected HUVECs (E4ECs) in serum free/growth factor free conditions . Co-culture of UCB CD34 + cells with the E4ECs in direct contact with minimal concentrations of hematopoietic cytokines resulted in a 150-fold expansion of hematopoietic progenitor cells that was 3-fold greater than the hematopoietic cytokines alone. Significantly greater primary and secondary engraftment of the expanded UCB CD34 + cells into immunodeficient mice was observed in the cells expanded on the E4ECs than in cultures with hematopoietic cytokines alone . Another group has identified CD146 + perivascular mesenchymal cells derived from human adult adipose tissue to provide in vitro co-culture support to expand the number of UCB CD34+ cells and to enhance engraftment into immunodeficient mice . Other approaches have been recently reviewed . In sum, a host of approaches are seeking to expand the stem cell pool within the UCB that may permit greater utilization of UCB as an alternative stem cell source for adult subjects that lack suitable donors. Methods to enhance UCB homing and engraftment One way to enhance the seeding of UCB cells into the bone marrow niches that are specialized for stem cells, is to directly inject the UCB into the bone marrow cells . Time to recovery of neutrophil and platelet counts has recently been shown to be significantly shortened in a comparison of patients undergoing an intra-bone UCB transplant versus a double UCB transplant . A significant reduction in acute GVHD was also reported in patients receiving the intra-bone UCB transplant . However, only a prospective study that employs a homogenous conditioning regimen and GVHD prophylaxis will permit determination of whether the intra-bone UCB versus double UCB transplantation approach provides a better outcome. An alternative choice for enhancing UCB transplant outcomes would be to enhance the homing of the cells into the marrow niche. A stable prostaglandin E 2 (PGE 2 ) derivative 16,16- dimethyl PGE 2 (dmpge 2 ) has been shown to enhance hematopoietic stem cell (HSC)
9 engraftment with some evidence for increased HSC homing and survival [29-32]. In a phase I trial recently completed, dmpge 2 treatment of a single UCB unit when administered with an unmanipulated UCB unit led to accelerated neutrophil recovery compared to historical controls and the dmpge 2 treated UCB unit outcompeted the unmanipulated UCB unit long term in 10 of 12 subjects . Based upon these results, the authors are proposing additional clinical trials of dmpge 2 to enhance engraftment of UCB and even autologous adult peripheral blood stem cells for transplantation. Homing of UCB cells may also be enhanced by treating the cells with fucosyltransferase- VI. UCB CD34 + cells displaying greater cell surface fucosylation displayed more rapid and higher levels of engraftment in immunodeficient mouse models compared to untreated UCB cells . These results have spawned a human clinical trial in which patients will receive a double UCB unit transplant in which one of the units is fucosylated . Dipeptidylpeptidase 4 (DPP4) is expressed on the cell surface of many cells, but inhibition of DPP4 on HSC enhances engraftment in preclinical studies . In a recent phase I trial, patients undergoing a single unit UCB transplant were administered sitagliptin (DPP4 inhibitor) orally prior to the UCB cell infusion. Systemic DPP4 inhibition was achieved and was well tolerated. A correlation between DPP4 activity time curve and time to engraftment was observed. Optimization of the DPP4 inhibition through manipulation of the oral agent may permit improved outcomes . UCB use for non-hematological disorders While the above discussion has outlined the important role UCB can play as a source of cells to repopulate the hematopoietic system in patients requiring such a therapy, UCB has been demonstrated to contain a variety of other cell types with stem cell properties . Mesenchymal stem/stromal cells (MSCs), multipotent adult progenitor cells, unrestricted somatic stem cells, and endothelial colony forming cells have all been isolated and
10 cryopreserved from UCB . A recent analysis of clinical trials using UCB for non-hematologic disorders has identified 31 unique trials for 15 different clinical conditions (Table) . Essentially all of the clinical trials have arisen from preclinical data obtained using animal models of human disease and in many cases, UCB or UCB-derived stem cell populations as therapeutic agents. Great interest has arisen over the potential use of autologous UCB to treat human neonates that suffer hypoxic-ischemic injury . Human clinical trials using this approach are underway, however, no reports of the outcomes of these trials are yet available . UCB banking ongoing controversies UCB continues to be banked largely in two separate systems: public or private cord blood banks. Public banks incur all the costs for collection, transportation, processing, testing, and cryopreservation. The inventory of the UCB units is listed through national and international registries and is intended to provide patients with a high quality unit if needed and matched. If a unit is selected for transplant, the public bank is compensated as a cost-recovery. Private cord blood banks charge a fee to parents for the collection, transportation, processing, testing, and cryopreservation of the material and some type of annual fee for the ongoing storage of the UCB unit. A comparison of the public and private banking processes has recently been published . Some controversy continues to exist around the cost-effectiveness of the private UCB banking system. One study has argued that use of autologous UCB units from private cord blood banks is extremely rare compared to use of allogeneic units from public banks and overall this leads to a much higher cost per unit used from the private over public banks [4, 42]. Furthermore, given the fact that most private banks are not subject to the same regulatory review as public banks, one cannot be assured that the UCB stored is of comparable quantity and quality when comparing private to public units. Hybrid UCB banking models have been
11 considered but also suffer from many ethical, regulatory, economic, and social concerns . However, hybrid UCB banking has been selected as a preferred model among some current and potential UCB donors . Some challenges persist in developing directed-family cord blood banking for those families who are pregnant and have an existing child or a known risk for producing a child affected by a disease that could be cured by allogeneic HSC transplantation . Conclusion Cord blood transplantation and banking have matured greatly in the first 25 years of application. It is obvious that cord blood banking models continue to be controversial and may continue to morph as the need for stored units increases worldwide. How UCB expansion technologies impact patient outcomes and usage may also factor into banking demands. As new fields of regenerative medicine test UCB as a potential source of reparative stem cells, even greater demand may be placed on the banking industry. It is anticipated that cord blood transplantation and banking will continue to advance along with the scientific progress.
12 Acknowledgements None.
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