Factors Influencing the Umbilical Cord Blood Stem Cell Industry: An Evolving Treatment Landscape

Abstract

Hematopoietic stem cell transplantation (HSCT) is common practice today for life threatening malignant and non-malignant diseases of the blood and immune systems. Umbilical cord blood (UCB) is rich in hematopoietic stem cells (HSCs) and is an attractive alternative to harvesting HSCs from bone marrow or when mobilized into peripheral blood. One of the most appealing attributes of UCB is that it can be banked for future use and hence provides an off-the-shelf solution for patients in urgent need of a transplantation. This has led to the establishment of publicly funded and private UCB banks, as seen by the rapid growth of the UCB industry in the early part of this century. However, from about 2010, the release of UCB units for treatment purposes plateaued and started to decrease year-on-year from 2013 to 2016. Our interest has been to investigate the factors contributing to these changes. Key drivers influencing the UCB industry include the emergence of haploidentical HSCT and the increasing use of UCB units for regenerative medicine purposes. Further influencing this dynamic is the high cost associated with UCB transplantation, the economic impact of sustaining public bank operations and an active private UCB banking sector. We foresee that these factors will continue in a tug-of-war fashion to shape and finally determine the fate of the UCB industry.

Introduction

The ability to successfully transplant hematopoietic stem cells (HSCs) in order to reconstitute the hematopoietic system is one of the major advances in medicine and has evolved considerably in recent years [1]. Hematopoietic stem cell transplantation (HSCT) is practiced for life threatening malignant and non-malignant diseases of the blood and immune systems [2]. These cells are procured either from the patient or a donor, and are used respectively for autologous or allogeneic transplantation. Donors for allogeneic HSCT can be either HLA-matched sibling donors (MSD) or HLA-matched unrelated donors (MUD). While MSD-HSCT generally renders better and safer outcomes, only 30% of patients have an HLA-matched sibling [2], which increases the need for MUDs. With the establishment of local and international donor registries, up to 75% of Caucasian patients are able to find a genetic match [3, 4]. This is however not the case for all patients, with less than 20% of patients from non-Caucasian groups being successful in finding an HLA-match [5]. Over and above the challenges faced in establishing a genetically diverse donor pool, registries are hampered by high donor attrition rates [6].

Although historically harvested directly from bone marrow (BM), HSCs are today mostly collected from peripheral blood, following a 4–5 days regimen with a mobilizing agent such as granulocyte colony stimulating factor. . Although umbilical cord blood (UCB) is a rich source of HSCs, it is usually discarded at birth [7, 8]. HSCs from UCB offer the advantage of requiring less stringent HLA-matching criteria (six loci, rather than 10 as is the case for BM-HSCs). In addition, since these cells can be cryopreserved, this provides an off-the-shelf solution to patients in urgent need of transplantation. These factors are particularly advantageous for patients from non-Caucasian ethnic groups [4, 7, 9, 10], especially since this offers access to a worldwide inventory and increased the likelihood of finding a match. The safety and efficacy of UCB-HSCT has been widely studied and established for both children and adults for a variety of indications. When compared to HSCT involving stem cells harvested from BM or mobilized into peripheral blood, UCB-HSCT has a lower risk of graft-versus-host-disease (GVHD), a common and often fatal complication of HSCT [7], as well as greater protection against disease relapse in various settings [11–13]. The primary disadvantage of using UCB is the low yield of HSCs when compared to BM or peripheral blood mobilized HSCs. Use of a sub-optimal HSC cell dose results in delayed hematological recovery, higher graft failure rates and risk of infection [4, 8]. This results in increased hospitalization times and a consequent increase in treatment costs. Double UCB transplantation is often employed to overcome this [14]. In addition, novel ex vivo manipulation strategies to either expand or improve the homing of UCB-derived HSCs are being explored in preclinical and clinical studies. For expansion, these include the coculture of UCB-derived HSCs with mesenchymal stem cells or small molecules such as stemregenin-1, nicotinamide and notch ligand, while to improve homing, molecules such as prostaglandin E-2, sitagliptin or fucosylation are being used [15]. The cost factor is particularly pertinent in the context of allogeneic UCB transplantation, when one considers that procurement of a single UCB unit can be in excess of USD 35,000. The costs of double UCB unit transplantation and further manipulations can therefore be prohibitively expensive. The recent licensure of UCB units by the FDA, that is, the classification of the product as a drug, is a further challenge and cost burdening factor for patients in the U.S. [16], as it requires that UCB banks demonstrate rigorous testing and qualification of their processed units in order to have their manufacturing facilities accredited.

One of the most appealing attributes of UCB is that the harvested units can be banked for future use following collection [17]. Three types of UCB banks exist, namely public, private, and hybrid (Table 1). Public banks store UCB units received altruistically from donors, which are then listed on international registries and made available for any potential recipient pending establishment of an adequate HLA match. In contrast, private banks, also referred to as family banks, store UCB for exclusive future use either by the donor or a matched relative. This limited use translates to low recall rates on UCB units. Private banks tend to overestimate the benefit of private banking. Marketing inaccuracies link the overall potential of stem cells to autologous cord blood despite the fact that indications for the use of autologous cord blood stem cells is at present limited. In addition, the industry is driven by subjective (emotional) factors. Finally, informed consent is often inadequate as it does not address these issues [18]. Hybrid banks offer combined public and private UCB storage solutions. In the first scenario, either the private bank offers a public donation or the public bank offers a private storage option. Alternative models include the following: (a) 25% of privately stored UCB is donated to the public system in accordance with national legislation (Turkish model); (b) UCB is stored privately but if an unrelated match is found the unit can then donated to the public (Spanish model); (c) harvested UCB units can be divided in two—one portion for exclusive use and the other for public use (Virgin model); and (d) UCB is stored for private use and at a later stage is released to the public following consent from the donor [18–21]. Either way, the public side of hybrid banks is generally cross-subsidized by income generated from its private activities.

It has been reported that more than 80 indications can be treated using UCB [9, 22, 23]. The scope of these indications has recently been extended beyond traditional applications of HSCT, and today includes several experimental strategies aimed at treating diseases such as cerebral palsy, type 1 diabetes and autism [17, 24, 25]. We have undertaken a historical analysis of the worldwide usage of UCB units in order to describe emerging trends and to provide an overview of factors shaping the UCB industry.

Evolving Treatment Landscape

Nearly 50,000 UCB units had been released by public banks for allogeneic transplantation purposes as of the end of 2016 (WMDA). The number of units released by private banks is unclear, but it is suggested that approximately 30 times fewer units have been released to date than from public banks [23]. From a historical perspective, UCB-HSCT started to gain momentum at the turn of the 21st century. More and more people with malignant and non-malignant hematologic disorders were being treated, and the use of UCB, particularly in the pediatric setting, was becoming well accepted. Accordingly, public, private, and hybrid UCB banks were being established globally to meet patient needs. At its peak, and during the period from 2011 to 2013, public banks held an inventory in excess of 700,000 UCB units and released approximately 4,100 UCB units per annum for allogeneic purposes (Fig. 1). Private banks in contrast have amassed nearly 4 million UCB units in inventory, but have on average released only 130 UCB units per annum for treatment [23]. When available, the data regarding the number of units released by hybrid banks is difficult to interpret. Many of the units released for private or public use are not specified under the hybrid model. Additionally, banks that offer hybrid banking are often classified as either public or private and not exclusively as a hybrid bank making it difficult to ascertain the exact number of hybrid banks.

From 2013 however, the release of UCB units decreased year-on-year, with the most recent data indicating that 3,274 units were shipped in 2016. Additionally, there has been a downturn in the number of UCB units being banked annually, resulting in a plateau in the global inventory of UCB units. Reasons for the decline are largely attributed to advances in haploidentical HSCT. In this approach, BM or peripheral blood mobilized HSPCs from a partially HLA-matched donor are used. Donors only need to be a 50% match to the recipient and are typically either the recipient's parents, siblings, or close relatives. Following transplantation, patients receive additional chemotherapy, anchored by high dose cyclophosphamide, to manage the risks of graft failure and GVHD. Given the high costs of procuring UCB units together with limitations in cell dose, and the ease with which a family member can be accessed for haploidentical transplantation, a decline in UCB-HSCT is argued to be an inevitable consequence of this procedure. An increase in haploidentical HSCT means a decrease in the need for UCB, which in turn may threaten the existence of UCB banks. This is particularly pertinent in the case of public banks, where 90% are unable to sustain themselves financially based on the sale of UCB units alone [26, 27].

The situation from a private UCB bank point of view is seemingly different. Although also impacted by the emergence of haploidentical HSCT, there has been a dramatic shift in the release of UCB units toward use for regenerative medicine purposes (Fig. 2). In fact, based on our analysis of data published by 19 of the largest private UCB banks (Table 2), over 65% of UCB units released in the last 5 years of reporting (2011–2015) have been for the treatment of non-hematological conditions. In public banks, no more than 10% of UCB units (2010–2014) were released for regenerative medicine purposes over a similar period [28–33].

These findings prompted us to investigate the scope of indications being treated with UCB. Indications were grouped into either of two treatment categories: transplantation or regenerative medicine (Table 3). Transplantation strategies included indications where UCB was used to replace or reconstitute cells of the blood and immune systems [34]. Indications are regarded as being for regenerative medicine purposes if UCB units are used to regenerate cells, tissues or organs by establishing or creating normal function after an injury or illness [34–36]. It is important to note that the use of UCB for regenerative medicine purposes is still regarded as experimental and in most cases is under investigation in clinical trials.

Our findings suggest that over 100 indications have in fact been treated with UCB, which is more than the 80 reported previously [9, 22, 23]. We have also been able to detail the stark contrast in treatment landscapes that utilize UCB units released from public and private banks (Fig. 3). Notably, public banks have released the greater proportion of their UCB units for the treatment of leukemia (>60%), while private banks released an equivalent percentage of their inventory for neurological conditions. Conversely, public banks released no more than 7% of their units for treating neurological conditions, and private banks less than 20% for leukemia (Fig. 3). These findings are all the more striking when one considers that leukemia is the most established indication for UCB-HSCT, and although considered a valid indication, the use of UCB for neurological disease is still experimental in nature. Although many of the reported treatments exploring the use of UCB for neurological conditions have been released by public and private banks in the U.S. (Fig. 3), units have also been released from non-U.S. public banks for neurological treatment outside of the U.S. From 2010 to 2011, roughly 105 unrelated UCB units were released from CHA Medical Center Cord Blood Bank in Korea for use in a clinical trial for cerebral palsy (NCT01193660) [37], and between 2004 and 2005, eight unrelated units were used in a pilot study for cerebral palsy in Mexico [38].

Treatment  of Neurological Disease  with UCB

The treatment of neurological diseases and brain injury with UCB is a trend that has grown appreciably in recent years. The rationale for treating these conditions is based on arguments that UCB is able to: (a) assist in regenerating damaged brain cells; (b) reduce the inflammatory and immune responses; (c) promote cell survival; (d) induce cell migration, proliferation, and differentiation; and (e) promote angiogenesis [37, 39, 40]. UCB is a heterogeneous mixture of cells, and apart from HSCs contains mesenchymal stem cells, endothelial progenitor cells, and other stromal precursor cells [41, 42]. It has been suggested that the entire mix of hematopoietic and non-hematopoietic multipotent progenitor cells (rather than an individual sub-population) is important for improving physiological function in disease and injury of the brain [37, 42, 43]. Mechanisms other than homing and engraftment have been explored using this mixture of cells and a therapeutic benefit via paracrine signaling has been observed [44–46]. Although treating neurological conditions with UCB is still experimental, positive outcomes have been reported in children with cerebral palsy and hypoxic ischemic encephalopathy, including improved cognitive and motor function [23, 37, 39, 45–47].

There are at least 18 clinical trials investigating the use of UCB for the treatment of neurological disorders [18]. The majority are investigating the use of UCB for cerebral palsy, followed by hypoxic-ischemic encephalopathy and autism. As the trials draw to a close, we will gain a better understanding as to whether UCB is indeed a viable option for these patients. If favorable, the number of UCB units released for these indications will almost certainly increase [16]. Cerebral palsy makes up the greatest proportion of neurological conditions treated with UCB (Fig. 4). Approximately 30% and over 35% of UCB units were released respectively in 2013 and 2014 from private banks for autism spectrum disorder. Last, private banks have every year, since 2005, released UCB units for the treatment of hypoxic ischemic encephalopathy, brain injury, and hydrocephalus.

Summary  and Outlook

The UCB industry has been influenced by a diverse range of factors. A period of rapid growth occurred as a result of the increasing acceptance of HSCT and the use of UCB as an alternative to BM-derived HSCs (harvested directly or following mobilization into peripheral blood). However, the emergence of haploidentical HSCT has resulted in a decline in the use of UCB and a plateau in global inventories. This downturn has been compensated for partially by an increase in the use of UCB for regenerative medicine purposes, albeit mostly in clinical trials. Adding to this dynamic is the question of economics. The high cost of allogeneic UCB transplantation is a challenge for many patients, which is further impacted by the FDA requirement for licensure of units in the U.S. For public banks, the cost of banking UCB units is only recovered if units are sold to HLA-matched recipients. Ongoing subsidies are thus necessary, and the fact that 90% of public banks are unable to self-sustain is clearly not conducive to growth. In contrast, private banks secure their income in advance or soon after banking UCB units, and hence sustainability is not dependent upon the sale of units. The net result is that the global inventory held by private banks exceeds four million units—nearly seven times that of public banks.

We foresee that use of haploidentical HSCT will continue to increase. This is likely to reduce UCB-HSCT and poses a significant threat to the public UCB bank industry, while the promise of regenerative medicine will remain a key driver for the growth in particular of private, but also of public UCB banks. The next decade will reveal the extent to which the use of UCB for regenerative medicine purposes will be able to turn the tide in a contracting, yet increasingly diversified treatment landscape.

Acknowledgments

We would like to thank the World Marrow Donor Association (WMDA) for kindly providing recent UCB storage and release data. This research and the publication thereof is the result of funding provided by the Medical Research Council of South Africa in terms of (a) the MRC's Flagships Awards Project SAMRC-RFA-UFSP-01–2013/STEM CELLS and (b) the Extramural Unit for Stem Cell Research and Therapy. Funding was also provided by the Institute for Cellular and Molecular Medicine, Faculty of Health Sciences, University of Pretoria.

Author Contributions

C.D. and M.A.: conception and design, collection and/or assembly of data, data analysis and interpretation, manuscript writing; M.S.P.: conception and design, fund raising, provision of study materials or patients, manuscript writing, final approval of manuscript.

Disclosure  of Potential Conflicts  of Interest

The authors indicated no potential conflicts of interest.

References