Elsevier

Cytotherapy

Volume 12, Issue 2, 2010, Pages 121-130
Cytotherapy

Overcoming the barriers to umbilical cord blood transplantation

https://doi.org/10.3109/14653240903440111Get rights and content

Abstract

Umbilical cord blood (UCB) transplantation (UCBT) has seen a marked increase in utilization in recent years, especially in the pediatric population; however, graft failure, delayed engraftment and profound delay in immune reconstitution leads to significant morbidity and mortality in adults. The lack of cells available for post-transplant therapies, such as donor lymphocyte infusions, has also been considered a disadvantage. To overcome the cell–dose barrier, the combination of two UCB units is becoming commonplace in adolescent and adult populations, and is currently being studied in pediatrics as well. In some studies, the use of two UCB units appears to have a positive impact on outcomes; however, engraftment is still suboptimal. A possible additional way to improve outcome and extend applicability of UCBT is via ex vivo expansion. Studies to develop optimal expansion conditions are still in the exploratory phase; however, recent studies suggest expanded UCB is safe and can improve outcomes. The ability to transplant across HLA disparities, rapid procurement time and decreased graft-versus-host disease (GvHD) seen with UCBT makes it a promising stem cell source and, while barriers exist, consistent progress is being made to overcome them.

Introduction

Umbilical cord blood (UCB) has become an important source of hematopoietic stem cell (HSC) support following myeloablative and non-myeloablative therapies (1., 2., 3.). UCB is rapidly available and appears to have a lower incidence of graft-versus-host disease (GvHD) despite HLA disparity. This makes it an attractive option for many patients, including patients with non-malignant disease where GvHD should be minimized and proceeding to transplant rapidly may be of prime importance. In addition, because of the allowance for greater HLA disparity than bone marrow (BM) or peripheral blood stem cell grafts, UCB has provided a significantly higher chance of finding a donor, especially for minority populations that are currently underrepresented in donor registries.

While the use of UCB as a stem cell source has seen a significant increase in recent years, especially in children and young adults, it is not without drawbacks. One of the major limitations of UCB as an HSC therapy is the low cell dose available for transplantation. It is now well documented that the total nucleated cell (TNC) dose transplanted per kilogram (kg) of body weight of the recipient correlates with outcomes (4., 5., 6.). As a consequence, UCB transplantation (UCBT) remains significantly more successful in children (5). Also, even in children receiving satisfactory cell doses, there is still often some delay in engraftment of all cell lines compared with traditional stem cell sources (7., 8., 9.) and in immune reconstitution (10,11), suggesting that, even in the optimal patient population, the low progenitor cell dose given with UCBT could have negative effects on outcomes.

In general there have been two approaches to overcome the obstacle of low TNC cell dose seen with UCBT. One has been to utilize more than one UCB unit in order to achieve a higher number of TNC available for infusion (12., 13., 14., 15.). Many trials are currently underway assessing the efficacy and outcomes in both adults and children (Table I). The second approach has been to attempt to expand UCB units ex vivo. Ex vivo expansion can be performed on either a portion of a UCB unit or the unit in its entirety, with the expanded cells infused either at the time of transplant of ‘unmanipulated’ fraction or given at a separate time. The manipulated UCB could be from either the same unit or, potentially, a different UCB unit. The combination of ex vivo-expanded fractions and unmanipulated UCB fractions might prove to be a beneficial strategy (16,17) and clinical trials are currently underway (18., 19., 20., 21., 22.) (Table II).

Section snippets

Double-unit UCBT

In an effort to overcome the issue of low cell dose with a single cord, case reports of combining cord blood units started appearing in the late 1990s (12,14,21., 22., 23., 24., 25., 26., 27., 28.). In early studies, up to 12 cord blood units were used per patient but, because of the cost of the units and resource allocation, two units are generally regarded as the standard in multiple cord blood protocols. To date, hundreds of double-unit UCBT (DUCBT) have been performed (29., 30., 31., 32.).

Ex vivo expansion

The goal of ex vivo expansion of cord blood is at least two-fold. The primary focus of expansion has been to generate sufficient numbers of HSC to optimize the graft available for transplant. Another important goal is to generate higher numbers of lineage-committed progenitor cells that, although transient, will allow rapid recovery from pancyotpenia, thus decreasing early morbidity and mortality. There is a concern that ex vivo-expanded products may possess an inherent reduction in long-term

Summary

Recently, trials have shown improved outcomes for UCBT. In pediatric patients, cord blood may even emerge as the preferred stem cell source. In adult patients more obstacles still exist; however, progress continues to be made. Combining cord blood units has allowed higher cell doses to be achieved, reduced graft failure rates and improved outcomes. Current clinical trials have demonstrated that the use of expanded UCB can be safe and recent results suggest the potential for improved outcomes;

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