REVIEW URRENT C OPINION
Cord blood banking and transplantation: advances and controversies Mervin C. Yoder
Purpose of review A review of articles published since January 2012 on the topic of cord blood banking and cord blood stem cell transplantation was conducted for this the 25th anniversary year of the first cord blood transplant performed in a human. 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 paediatric and adults requiring a haematopoietic 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 nonhaematopoietic indications may increase demand for UCB over the next few decades. Keywords cord blood stem cell transplantation, umbilical cord blood, umbilical cord blood banking
INTRODUCTION This has been a notable year for cord blood transplantation and banking, since it was 25 years ago that a child with Fanconi anaemia 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 more than 30 000 transplants have been performed using stored material [1 ]. 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 wherein UCB has been proposed as a novel source of stem cells that may provide repair or regeneration of tissue function in nonhaematopoietic 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 [1 ]. A child with Fanconi anaemia who was suffering from severe aplastic anaemia was deemed a potentially suitable candidate when a tissuematched 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 &&
Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana, USA Correspondence to Mervin C. Yoder, MD, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA. Tel: +1 317 274 4738; e-mail: [email protected] Curr Opin Pediatr 2014, 26:163–168 DOI:10.1097/MOP.0000000000000065
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KEY POINTS Cord blood is increasingly utilized as a source for stem cell transplantation. Expanded cord blood products are demonstrating efficacy in reducing time to engraftment in some transplanted patients. Nonhaematopoietic indications for cord blood products is an emerging field of investigation and a potential novel pathway for tissue repair and regeneration.
Fanconi anaemia. Dr Eliane Gluckman had previously developed pretransplant conditioning regimens for patients with Fanconi anaemia 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 posttransplant and subsequently achieved a full haematopoietic reconstitution with donor cells. Now 25 years later, this healthy patient continues to show complete haematologic and immunologic donor cell chimerism [1 ]. Several years after this epic event, the first public UCB bank was formed at the New York Blood Center [3], and in 1993, the first unrelated UCB transplant was performed [4,5]. Subsequently, UCB was increasingly utilized in paediatric 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 [6]. In a recent analysis of 5-year outcomes of children with acute leukaemia who received a sibling UCB transplant, the probability of disease-free survival (DFS) was 44% [7]. In children with acute leukaemia who received either an unrelated matched UCB or an unrelated matched bone marrow transplant, recipients of the UCB had better outcomes [8]. An increase in transplant-related mortality (TRM) was detected in children receiving less than 3 107 total nucleated cells per kilogram bodyweight and a one human leukocyte antigen (HLA)-disparate match or in children given a two HLA-disparate UCB transplant, pointing out the importance of UCB unit selection for improving outcomes [8]. 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 paediatric patients with a haematologic malignancy did not show a survival advantage [1 ,9]. Use of UCB as a stem cell source in adult patients with leukaemia failed to result in the promising &&
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results obtained in paediatric patients with concerns that the neutrophil and platelet recovery times were significantly delayed and there was high TRM [10]. 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 adults identified older age, advanced disease and limited centre experience correlated with worse survival [11]. However, a remarkable 60–70% 5-year DFS was reported by one group from Japan for adult patients with acute myelogenous leukaemia (AML) who underwent myeloablative conditioning prior to receiving a single UCB transplant [12]. To improve outcomes in the USA, combining reduced intensity conditioning with double cord blood transplantation has resulted in 30–50% DFS in adults with malignancy [13 ,14]. Improvements in UCB unit selection are expected to further enhance outcomes in adults who need a UCB transplant [15]. Thus, one recent review recommends that UCB transplantation should be considered in all highrisk adults with AML in whom an allogeneic stem cell transplant is indicated but who lack a matched related or unrelated donor [1 ]. &
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METHODS TO EXPAND UMBILICAL CORD BLOOD HAEMATOPOIETIC STEM CELLS Given the delayed donor cell reconstitution of UCB recipients and the associated increased incidence of late viral infections and other TRM [16], 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. &
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NOTCH-MEDIATED EXPANSION OF UMBILICAL CORD BLOOD CAPABLE OF RAPID MYELOID RECONSTITUTION Activation of endogenous Notch receptors on UCB CD34þ cells via coculture on immobilized engineered Delta-like ligand 1 was known to increase the CD34þ content nearly 100-fold and to increase the engraftment of the Notch-activated cells in immunodeficient mice [19]. In preliminary clinical studies, use of the same approach provided a significant expansion of UCB CD34þ cells and when coinfused with an unmanipulated UCB unit, reduced the time to an absolute neutrophil count (ANC) of more than 500 cells/ml to a median of 16 days. This time was significantly reduced Volume 26 Number 2 April 2014
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compared with a median of 26 days for ANC recovery in patients concurrently treated at the same institution with a double UCB transplant [20]. 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 with 25 days in a concurrently enrolled institutional cohort of 36 patients undergoing a double UCB transplant [18 ]. As the expanded unit predominated during the first week posttransplant, evidence exists that the Notch-activated UCB cells provide rapid myeloid recovery. &&
expand UCB. A purine molecule name StemRegenin1 (SR1) was identified in an unbiased screen of 100 000 compounds to expand CD34þ cells. UCB cells treated with SR1 demonstrated a 50-fold increase in CD34þ cells and a 17-fold increase in UCB cells that repopulate immunodeficient mice and may be one promising agent to expand UCB [24]. In another approach, human umbilical vein endothelial cells (HUVECs) were infected with a 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 [25 ]. Co-culture of UCB CD34þ cells with the E4ECs in direct contact with minimal concentrations of haematopoietic cytokines resulted in a 150-fold expansion of haematopoietic progenitor cells that was three-fold greater than the haematopoietic cytokines alone. Significantly greater primary and secondary engraftment of the expanded UCB CD34þ cells into immunodeficient mice was observed in the cells expanded on the E4ECs than in cultures with haematopoietic cytokines alone [25 ]. Another group has used CD146þ perivascular mesenchymal cells derived from human adult adipose tissue to provide in-vitro coculture support to expand the number of UCB CD34þ cells and to enhance engraftment into immunodeficient mice [26]. Other approaches have been recently reviewed [17 ]. 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 adults who lack suitable donors. &
UMBILICAL CORD BLOOD ENGRAFTMENT WITH EX-VIVO MESENCHYMAL-CELL COCULTURE Expansion of haematopoietic progenitor cells in unfractionated UCB cells is markedly enhanced upon coculture with mesenchymal stromal cells [21]. In a recent study, 31 adults with haematological cancer who received a UCB transplant with one expanded unit and one unmanipulated unit were compared with 80 historical controls who received two unmanipulated UCB units. The median time to neutrophil engraftment was 15 days in the patients who received the expanded unit along with the unmanipulated unit compared with 24 days in the control patients who received a double UCB unit transplant, a significant improvement [22 ]. 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 as well as unmanipulated UCB. Of interest, the dose of the CD34þ 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 adults [22 ]. &
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METHODS TO ENHANCE UMBILICAL CORD BLOOD 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 [27]. Time to recovery of neutrophil and platelet counts was significantly reduced in a comparison of patients undergoing an intrabone UCB transplant versus a double UCB transplant [28 ]. A significant reduction in acute GVHD was also reported in patients receiving the intrabone UCB transplant [28 ]. However, only a prospective study that employs a homogenous conditioning regimen and GVHD prophylaxis will permit determination of whether the intrabone 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 E2 (PGE2) derivative 16,16-dimethyl PGE2 &
OTHER APPROACHES TO EXPAND UMBILICAL CORD BLOOD 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 [23]. A number of preclinical studies have provided promising pathways to
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(dmPGE2) has been shown to enhance haematopoietic stem cell (HSC) engraftment with some evidence for increased HSC homing and survival [29–32]. In a phase I trial recently completed, dmPGE2 treatment of a single UCB unit when administered with an unmanipulated UCB unit led to accelerated neutrophil recovery compared with historical controls. Furthermore, the dmPGE2 treated UCB unit outcompeted the unmanipulated UCB unit long term in 10 out of 12 individuals [33 ]. On the basis of these results, the authors are proposing additional clinical trials of dmPGE2 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 CD34þ cells displaying greater cell surface fucosylation displayed more rapid and higher levels of engraftment in immunodeficient mouse models than in untreated UCB cells [34]. 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 [18 ]. Dipeptidylpeptidase 4 (DPP4) is expressed on the cell surface of many cells, but inhibition of DPP4 on HSC enhances engraftment in preclinical studies [35]. 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 &
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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 [36].
UMBILICAL CORD BLOOD USE FOR NONHAEMATOLOGICAL DISORDERS Although the above discussion has outlined the important role UCB can play as a source of cells to repopulate the haematopoietic system in patients requiring such a therapy, UCB has been demonstrated to contain a variety of other cell types with stem cell properties [37 ]. Mesenchymal stem/stromal cells (MSCs), multipotent adult progenitor cells, unrestricted somatic stem cells and endothelial colony forming cells have all been isolated and cryopreserved from UCB [38 ]. A recent analysis of clinical trials using UCB for nonhaematologic disorders has identified 31 unique trials for 15 different clinical conditions (Table 1) [38 ]. 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 who suffer hypoxic-ischemic injury [39 ]. Human clinical trials using this approach are underway; however, no reports of the outcomes of these trials are yet available [40 ]. &
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Table 1. Clinical trials using umbilical cord blood stem cells in therapy of nonhaematological disorders Condition
ClinicalTrials.gov Identifier
No.
Alzheimer’s disease
NCT01297218
1
Autism
NCT01343511
1
Bronchopulmonary dysplasia
NCT01297205
1
Burns
NCT01443689
1
Cartilage injury, osteoarthritis
NCT01041001
1
Cerebral palsy
NCT01072370; NCT01193660
2
Critical limb ischemia
NCT01019681
1
Diabetes
NCT01350219; NCT01415726; NCT00873925; NCT00989547
4
Epidermolysis bullosa
NCT01033552; NCT00881556; NCT00478244
3
Hearing loss
NCT01343394
1
Inborn metabolic disorders
8
Osteopetrosis
NCT00950846a; NCT00920972a; NCT01238328; NCT00668564; NCT00654433; NCT00383448; NCT00176917; NCT00176904 NCT00775931; NCT01087398; NCT00638820
Solid tumours
NCT00436761; NCT00112645
2
Stroke
NCT01438593
1
SLE, systemic sclerosis
NCT00684255
1
3
SLE, systemic lupus erythematosus. a Clinical trials that involve both haematological and nonhaematological disorders. && Reprinted with permission from [38 ].
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UMBILICAL CORD BLOOD 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 [41]. 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 with 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 with public units. Hybrid UCB banking models have been considered but also suffer from many ethical, regulatory, economic and social concerns [4]. However, hybrid UCB banking has been selected as a preferred model among some current and potential UCB donors [43]. 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 who could be cured by allogeneic HSC transplantation [4].
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.
Acknowledgements None. Conflicts of interest There are no conflicts of interest.
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Neonatology and perinatology 19. Delaney C, Varnum-Finney B, Aoyama K, et al. Dose-dependent effects of the Notch ligand Delta1 on ex vivo differentiation and in vivo marrow repopulating ability of cord blood cells. Blood 2005; 106:2693–2699. 20. Delaney C, Heimfeld S, Brashem-Stein C, et al. Notch-mediated expansion of human cord blood progenitor cells capable of rapid myeloid reconstitution. Nat Med 2010; 16:232–236. 21. Robinson SN, Ng J, Niu T, et al. Superior ex vivo cord blood expansion following co-culture with bone marrow-derived mesenchymal stem cells. Bone Marrow Transplant 2006; 37:359–366. 22. de Lima M, McNiece I, Robinson SN, et al. Cord-blood engraftment with ex & vivo mesenchymal-cell coculture. N Engl J Med 2012; 367:2305–2315. The first human clinical trial to demonstrate improved engraftment neutrophils and platelet times for cord blood stem cells expanded on mesenchymal cells and then transplanted into adult patients. 23. de Lima M, McMannis J, Gee A, et al. Transplantation of ex vivo expanded cord blood cells using the copper chelator tetraethylenepentamine: a phase I/II clinical trial. Bone Marrow Transplant 2008; 41:771–778. 24. Boitano AE, Wang J, Romeo R, et al. Aryl hydrocarbon receptor antagonists promote the expansion of human hematopoietic stem cells. Science 2010; 329:1345–1348. 25. Butler JM, Gars EJ, James DJ, et al. Development of a vascular niche platform & for expansion of repopulating human cord blood stem and progenitor cells. Blood 2012; 120:1344–1347. A novel preclinical study approach to expanding cord blood stem cells using modified HUVECs as a supportive monolayer. 26. Corselli M, Chin CJ, Parekh C, et al. Perivascular support of human hematopoietic stem/progenitor cells. Blood 2013; 121:2891–2901. 27. Frassoni F, Gualandi F, Podesta M, et al. Direct intrabone transplant of unrelated cord-blood cells in acute leukaemia: a phase I/II study. Lancet Oncol 2008; 9:831–839. 28. Rocha V, Labopin M, Ruggeri A, et al. Unrelated cord blood transplantation: & outcomes after single-unit intrabone injection compared with double-unit intravenous injection in patients with hematological malignancies. Transplantation 2013; 95:1284–1291. A study on the results of a direct comparison of cord blood cells administered via direct intrabone injections versus a double cord blood unit transplant. This study discusses how the present results need to be further evaluated using more standard approaches to patient care and transplantation protocols. 29. Goessling W, Allen RS, Guan X, et al. Prostaglandin E2 enhances human cord blood stem cell xenotransplants and shows long-term safety in preclinical nonhuman primate transplant models. Cell Stem Cell 2011; 8:445– 458. 30. Hoggatt J, Singh P, Sampath J, Pelus LM. Prostaglandin E2 enhances hematopoietic stem cell homing, survival, and proliferation. Blood 2009; 113:5444–5455. 31. North TE, Goessling W, Walkley CR, et al. Prostaglandin E2 regulates vertebrate haematopoietic stem cell homeostasis. Nature 2007; 447:1007–1011.
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32. Pelus LM, Hoggatt J, Singh P. Pulse exposure of haematopoietic grafts to prostaglandin E2 in vitro facilitates engraftment and recovery. Cell Prolif 2011; 44 (Suppl 1):22–29. 33. Cutler C, Multani P, Robbins D, et al. Prostaglandin-modulated umbilical cord & blood hematopoietic stem cell transplantation. Blood 2013; 122:3074– 3081. A very recent study on the improved engraftment provided by prostaglandintreated cord blood stem cells upon transplantation into humans. 34. Robinson SN, Simmons PJ, Thomas MW, et al. Ex vivo fucosylation improves human cord blood engraftment in NOD-SCID IL-2Rgamma(null) mice. Exp Hematol 2012; 40:445–456. 35. Christopherson KW 2nd, Hangoc G, Mantel CR, Broxmeyer HE. Modulation of hematopoietic stem cell homing and engraftment by CD26. Science 2004; 305:1000–1003. 36. Farag SS, Srivastava S, Messina-Graham S, et al. In vivo DPP-4 inhibition to enhance engraftment of single-unit cord blood transplants in adults with hematological malignancies. Stem Cells Dev 2013; 22:1007–1015. 37. Pelosi E, Castelli G, Testa U. Human umbilical cord is a unique and safe & source of various types of stem cells suitable for treatment of hematological diseases and for regenerative medicine. Blood Cells Mol Dis 2012; 49:20– 28. A concise overview of various stem cell populations for multiple lineages of cells that may be useful in regenerative medicine treatments. 38. Ilic D, Miere C, Lazic E. Umbilical cord blood stem cells: clinical trials in && nonhematological disorders. Br Med Bull 2012; 102:43–57. An outstanding concise overview of the clinical trials of UCB cells for nonhaematologic conditions. 39. Carroll J. Human cord blood for the hypoxic-ischemic neonate. Pediatric Res & 2012; 71 (4 Pt 2):459–463. This study presents evidence from preclinical studies performed with UCB in rodents exposed to hypoxia-ischemia that supports consideration of human clinical trials. 40. Liao Y, Cotten M, Tan S, et al. Rescuing the neonatal brain from hypoxic injury & with autologous cord blood. Bone Marrow Transpl 2013; 48:890–900. Timely analysis of the results of preclinical animal models of human hypoxiaischemia and provides rationale for considering human clinical trials of autologous cord blood transplantation for neonates with hypoxic-ischemic injury. 41. Guindi ES. Public and private cord blood banking. In: Broxmeyer HE, editor. Cord blood: biology, transplantation, banking, and regulation. Bethesda, MD: AABB Press; 2011. pp. 595–631. 42. Rosenthal J, Woolfrey AE, Pawlowska A, et al. Hematopoietic cell transplantation with autologous cord blood in patients with severe aplastic anemia: an opportunity to revisit the controversy regarding cord blood banking for private use. Pediatric Blood Cancer 2011; 56:1009–1012. 43. Wagner AM, Krenger W, Suter E, et al. High acceptance rate of hybrid allogeneic-autologous umbilical cord blood banking among actual and potential Swiss donors. Transfusion 2013; 53:1510–1519.
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Cord blood banking and transplantation: advances and controversies Mervin C. Yoder
Purpose of review A review of articles published since January 2012 on the topic of cord blood banking and cord blood stem cell transplantation was conducted for this the 25th anniversary year of the first cord blood transplant performed in a human. 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 paediatric and adults requiring a haematopoietic 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 nonhaematopoietic indications may increase demand for UCB over the next few decades. Keywords cord blood stem cell transplantation, umbilical cord blood, umbilical cord blood banking
INTRODUCTION This has been a notable year for cord blood transplantation and banking, since it was 25 years ago that a child with Fanconi anaemia 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 more than 30 000 transplants have been performed using stored material [1 ]. 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 wherein UCB has been proposed as a novel source of stem cells that may provide repair or regeneration of tissue function in nonhaematopoietic 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 [1 ]. A child with Fanconi anaemia who was suffering from severe aplastic anaemia was deemed a potentially suitable candidate when a tissuematched 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 &&
Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana, USA Correspondence to Mervin C. Yoder, MD, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA. Tel: +1 317 274 4738; e-mail: [email protected] Curr Opin Pediatr 2014, 26:163–168 DOI:10.1097/MOP.0000000000000065
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Neonatology and perinatology
KEY POINTS Cord blood is increasingly utilized as a source for stem cell transplantation. Expanded cord blood products are demonstrating efficacy in reducing time to engraftment in some transplanted patients. Nonhaematopoietic indications for cord blood products is an emerging field of investigation and a potential novel pathway for tissue repair and regeneration.
Fanconi anaemia. Dr Eliane Gluckman had previously developed pretransplant conditioning regimens for patients with Fanconi anaemia 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 posttransplant and subsequently achieved a full haematopoietic reconstitution with donor cells. Now 25 years later, this healthy patient continues to show complete haematologic and immunologic donor cell chimerism [1 ]. Several years after this epic event, the first public UCB bank was formed at the New York Blood Center [3], and in 1993, the first unrelated UCB transplant was performed [4,5]. Subsequently, UCB was increasingly utilized in paediatric 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 [6]. In a recent analysis of 5-year outcomes of children with acute leukaemia who received a sibling UCB transplant, the probability of disease-free survival (DFS) was 44% [7]. In children with acute leukaemia who received either an unrelated matched UCB or an unrelated matched bone marrow transplant, recipients of the UCB had better outcomes [8]. An increase in transplant-related mortality (TRM) was detected in children receiving less than 3 107 total nucleated cells per kilogram bodyweight and a one human leukocyte antigen (HLA)-disparate match or in children given a two HLA-disparate UCB transplant, pointing out the importance of UCB unit selection for improving outcomes [8]. 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 paediatric patients with a haematologic malignancy did not show a survival advantage [1 ,9]. Use of UCB as a stem cell source in adult patients with leukaemia failed to result in the promising &&
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results obtained in paediatric patients with concerns that the neutrophil and platelet recovery times were significantly delayed and there was high TRM [10]. 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 adults identified older age, advanced disease and limited centre experience correlated with worse survival [11]. However, a remarkable 60–70% 5-year DFS was reported by one group from Japan for adult patients with acute myelogenous leukaemia (AML) who underwent myeloablative conditioning prior to receiving a single UCB transplant [12]. To improve outcomes in the USA, combining reduced intensity conditioning with double cord blood transplantation has resulted in 30–50% DFS in adults with malignancy [13 ,14]. Improvements in UCB unit selection are expected to further enhance outcomes in adults who need a UCB transplant [15]. Thus, one recent review recommends that UCB transplantation should be considered in all highrisk adults with AML in whom an allogeneic stem cell transplant is indicated but who lack a matched related or unrelated donor [1 ]. &
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METHODS TO EXPAND UMBILICAL CORD BLOOD HAEMATOPOIETIC STEM CELLS Given the delayed donor cell reconstitution of UCB recipients and the associated increased incidence of late viral infections and other TRM [16], 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. &
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NOTCH-MEDIATED EXPANSION OF UMBILICAL CORD BLOOD CAPABLE OF RAPID MYELOID RECONSTITUTION Activation of endogenous Notch receptors on UCB CD34þ cells via coculture on immobilized engineered Delta-like ligand 1 was known to increase the CD34þ content nearly 100-fold and to increase the engraftment of the Notch-activated cells in immunodeficient mice [19]. In preliminary clinical studies, use of the same approach provided a significant expansion of UCB CD34þ cells and when coinfused with an unmanipulated UCB unit, reduced the time to an absolute neutrophil count (ANC) of more than 500 cells/ml to a median of 16 days. This time was significantly reduced Volume 26 Number 2 April 2014
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Cord blood banking and transplantation Yoder
compared with a median of 26 days for ANC recovery in patients concurrently treated at the same institution with a double UCB transplant [20]. 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 with 25 days in a concurrently enrolled institutional cohort of 36 patients undergoing a double UCB transplant [18 ]. As the expanded unit predominated during the first week posttransplant, evidence exists that the Notch-activated UCB cells provide rapid myeloid recovery. &&
expand UCB. A purine molecule name StemRegenin1 (SR1) was identified in an unbiased screen of 100 000 compounds to expand CD34þ cells. UCB cells treated with SR1 demonstrated a 50-fold increase in CD34þ cells and a 17-fold increase in UCB cells that repopulate immunodeficient mice and may be one promising agent to expand UCB [24]. In another approach, human umbilical vein endothelial cells (HUVECs) were infected with a 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 [25 ]. Co-culture of UCB CD34þ cells with the E4ECs in direct contact with minimal concentrations of haematopoietic cytokines resulted in a 150-fold expansion of haematopoietic progenitor cells that was three-fold greater than the haematopoietic cytokines alone. Significantly greater primary and secondary engraftment of the expanded UCB CD34þ cells into immunodeficient mice was observed in the cells expanded on the E4ECs than in cultures with haematopoietic cytokines alone [25 ]. Another group has used CD146þ perivascular mesenchymal cells derived from human adult adipose tissue to provide in-vitro coculture support to expand the number of UCB CD34þ cells and to enhance engraftment into immunodeficient mice [26]. Other approaches have been recently reviewed [17 ]. 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 adults who lack suitable donors. &
UMBILICAL CORD BLOOD ENGRAFTMENT WITH EX-VIVO MESENCHYMAL-CELL COCULTURE Expansion of haematopoietic progenitor cells in unfractionated UCB cells is markedly enhanced upon coculture with mesenchymal stromal cells [21]. In a recent study, 31 adults with haematological cancer who received a UCB transplant with one expanded unit and one unmanipulated unit were compared with 80 historical controls who received two unmanipulated UCB units. The median time to neutrophil engraftment was 15 days in the patients who received the expanded unit along with the unmanipulated unit compared with 24 days in the control patients who received a double UCB unit transplant, a significant improvement [22 ]. 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 as well as unmanipulated UCB. Of interest, the dose of the CD34þ 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 adults [22 ]. &
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METHODS TO ENHANCE UMBILICAL CORD BLOOD 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 [27]. Time to recovery of neutrophil and platelet counts was significantly reduced in a comparison of patients undergoing an intrabone UCB transplant versus a double UCB transplant [28 ]. A significant reduction in acute GVHD was also reported in patients receiving the intrabone UCB transplant [28 ]. However, only a prospective study that employs a homogenous conditioning regimen and GVHD prophylaxis will permit determination of whether the intrabone 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 E2 (PGE2) derivative 16,16-dimethyl PGE2 &
OTHER APPROACHES TO EXPAND UMBILICAL CORD BLOOD 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 [23]. A number of preclinical studies have provided promising pathways to
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Neonatology and perinatology
(dmPGE2) has been shown to enhance haematopoietic stem cell (HSC) engraftment with some evidence for increased HSC homing and survival [29–32]. In a phase I trial recently completed, dmPGE2 treatment of a single UCB unit when administered with an unmanipulated UCB unit led to accelerated neutrophil recovery compared with historical controls. Furthermore, the dmPGE2 treated UCB unit outcompeted the unmanipulated UCB unit long term in 10 out of 12 individuals [33 ]. On the basis of these results, the authors are proposing additional clinical trials of dmPGE2 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 CD34þ cells displaying greater cell surface fucosylation displayed more rapid and higher levels of engraftment in immunodeficient mouse models than in untreated UCB cells [34]. 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 [18 ]. Dipeptidylpeptidase 4 (DPP4) is expressed on the cell surface of many cells, but inhibition of DPP4 on HSC enhances engraftment in preclinical studies [35]. 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 &
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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 [36].
UMBILICAL CORD BLOOD USE FOR NONHAEMATOLOGICAL DISORDERS Although the above discussion has outlined the important role UCB can play as a source of cells to repopulate the haematopoietic system in patients requiring such a therapy, UCB has been demonstrated to contain a variety of other cell types with stem cell properties [37 ]. Mesenchymal stem/stromal cells (MSCs), multipotent adult progenitor cells, unrestricted somatic stem cells and endothelial colony forming cells have all been isolated and cryopreserved from UCB [38 ]. A recent analysis of clinical trials using UCB for nonhaematologic disorders has identified 31 unique trials for 15 different clinical conditions (Table 1) [38 ]. 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 who suffer hypoxic-ischemic injury [39 ]. Human clinical trials using this approach are underway; however, no reports of the outcomes of these trials are yet available [40 ]. &
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Table 1. Clinical trials using umbilical cord blood stem cells in therapy of nonhaematological disorders Condition
ClinicalTrials.gov Identifier
No.
Alzheimer’s disease
NCT01297218
1
Autism
NCT01343511
1
Bronchopulmonary dysplasia
NCT01297205
1
Burns
NCT01443689
1
Cartilage injury, osteoarthritis
NCT01041001
1
Cerebral palsy
NCT01072370; NCT01193660
2
Critical limb ischemia
NCT01019681
1
Diabetes
NCT01350219; NCT01415726; NCT00873925; NCT00989547
4
Epidermolysis bullosa
NCT01033552; NCT00881556; NCT00478244
3
Hearing loss
NCT01343394
1
Inborn metabolic disorders
8
Osteopetrosis
NCT00950846a; NCT00920972a; NCT01238328; NCT00668564; NCT00654433; NCT00383448; NCT00176917; NCT00176904 NCT00775931; NCT01087398; NCT00638820
Solid tumours
NCT00436761; NCT00112645
2
Stroke
NCT01438593
1
SLE, systemic sclerosis
NCT00684255
1
3
SLE, systemic lupus erythematosus. a Clinical trials that involve both haematological and nonhaematological disorders. && Reprinted with permission from [38 ].
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Cord blood banking and transplantation Yoder
UMBILICAL CORD BLOOD 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 [41]. 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 with 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 with public units. Hybrid UCB banking models have been considered but also suffer from many ethical, regulatory, economic and social concerns [4]. However, hybrid UCB banking has been selected as a preferred model among some current and potential UCB donors [43]. 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 who could be cured by allogeneic HSC transplantation [4].
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.
Acknowledgements None. Conflicts of interest There are no conflicts of interest.
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32. Pelus LM, Hoggatt J, Singh P. Pulse exposure of haematopoietic grafts to prostaglandin E2 in vitro facilitates engraftment and recovery. Cell Prolif 2011; 44 (Suppl 1):22–29. 33. Cutler C, Multani P, Robbins D, et al. Prostaglandin-modulated umbilical cord & blood hematopoietic stem cell transplantation. Blood 2013; 122:3074– 3081. A very recent study on the improved engraftment provided by prostaglandintreated cord blood stem cells upon transplantation into humans. 34. Robinson SN, Simmons PJ, Thomas MW, et al. Ex vivo fucosylation improves human cord blood engraftment in NOD-SCID IL-2Rgamma(null) mice. Exp Hematol 2012; 40:445–456. 35. Christopherson KW 2nd, Hangoc G, Mantel CR, Broxmeyer HE. Modulation of hematopoietic stem cell homing and engraftment by CD26. Science 2004; 305:1000–1003. 36. Farag SS, Srivastava S, Messina-Graham S, et al. In vivo DPP-4 inhibition to enhance engraftment of single-unit cord blood transplants in adults with hematological malignancies. Stem Cells Dev 2013; 22:1007–1015. 37. Pelosi E, Castelli G, Testa U. Human umbilical cord is a unique and safe & source of various types of stem cells suitable for treatment of hematological diseases and for regenerative medicine. Blood Cells Mol Dis 2012; 49:20– 28. A concise overview of various stem cell populations for multiple lineages of cells that may be useful in regenerative medicine treatments. 38. Ilic D, Miere C, Lazic E. Umbilical cord blood stem cells: clinical trials in && nonhematological disorders. Br Med Bull 2012; 102:43–57. An outstanding concise overview of the clinical trials of UCB cells for nonhaematologic conditions. 39. Carroll J. Human cord blood for the hypoxic-ischemic neonate. Pediatric Res & 2012; 71 (4 Pt 2):459–463. This study presents evidence from preclinical studies performed with UCB in rodents exposed to hypoxia-ischemia that supports consideration of human clinical trials. 40. Liao Y, Cotten M, Tan S, et al. Rescuing the neonatal brain from hypoxic injury & with autologous cord blood. Bone Marrow Transpl 2013; 48:890–900. Timely analysis of the results of preclinical animal models of human hypoxiaischemia and provides rationale for considering human clinical trials of autologous cord blood transplantation for neonates with hypoxic-ischemic injury. 41. Guindi ES. Public and private cord blood banking. In: Broxmeyer HE, editor. Cord blood: biology, transplantation, banking, and regulation. Bethesda, MD: AABB Press; 2011. pp. 595–631. 42. Rosenthal J, Woolfrey AE, Pawlowska A, et al. Hematopoietic cell transplantation with autologous cord blood in patients with severe aplastic anemia: an opportunity to revisit the controversy regarding cord blood banking for private use. Pediatric Blood Cancer 2011; 56:1009–1012. 43. Wagner AM, Krenger W, Suter E, et al. High acceptance rate of hybrid allogeneic-autologous umbilical cord blood banking among actual and potential Swiss donors. Transfusion 2013; 53:1510–1519.
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