Cord Blood Graft Engineering

Abstract

Once considered solely medical waste and routinely discarded as part of the afterbirth, umbilical cord blood (CB) is now commonly used as a source of hematopoietic stem cells (HSCs) for patients in need of HSC transplantation (HSCT) (or, as more commonly referred to, bone marrow transplantation) for the treatment of both malignant and nonmalignant disorders. In fact, more than 20,000 CB transplantations (CBTs) have been performed since the first one in 1988 [1], and this number increases annually as more recent data demonstrate outcomes for CBT recipients paralleling those for conventional HSCT recipients. Numerous factors make CB a desirable source of HSCs, including ease of procurement and lack of donor attrition, with the ability to process and store the donor cells long term [2]. Importantly, CB donors can be used without the need for a “perfect” HLA match, thereby increasing donor access to HSCT, particularly for minority and mixed ethnicity patients, for whom a suitably matched related or unrelated donor may be difficult to locate. Moreover, despite the greater degree of HLA mismatch, CBT recipients are at decreased risk of developing chronic graft-versus-host disease (GVHD). The first decade of CBT experience was important in defining critical total nucleated cell (TNC) and CD34+ cell dose thresholds required for acceptable clinical outcomes, and in moving from related to unrelated donor CBT and from pediatric to adult patients. The limitations of this approach also were defined during this period, with low cell dose identified as the critical barrier. CBT recipients receive on average only 10% of the CD34+ stem/progenitor cells provided in conventional bone marrow grafts and only 5% of those provided in peripheral blood stem cell grafts, resulting in significant delays in engraftment and immune reconstitution, as well as an increased risk of graft failure and early transplantation-related mortality. Despite these limitations, the second decade of CBT was marked by improved outcomes, especially in adults, as better knowledge of cell dose requirements led to improved collection and the availability of units with higher cell doses. Better supportive care also contributed to these improved outcomes. Initial reports showed outcomes for CBT recipients on par with conventional HSCT recipients [3-5]. Finally, the advent of double CBT (dCBT) brought a significant reduction in the risk of graft failure, opening up the possibility of HSCT with CB for essentially all patients without a suitable donor [6]. Nonetheless, the use of dCBT did not produce faster neutrophil recovery or immune reconstitution, with cell dose remaining a major limitation. The advent of dCBT has, however, led to increased activity in the area of CB graft engineering, especially in the area of ex vivo expansion, with the double-unit platform allowing for manipulation of 1 unit and the ability to track both units in vivo. Ex vivo expansion of CB stem and progenitor cells to enhance engraftment is only one area of CB graft engineering currently under clinical investigation. As discussed below in more detail, the generation of immunotherapy from CB grafts is under active investigation both preclinically and now in the clinic as a means of overcoming the issues of delayed immune reconstitution in CBT recipients, with the generation of multivirus-specific cytotoxic T lymphocytes to treat viral infections. Relapse also remains a problem for all patients undergoing HSCT for hematologic malignancy. The ex vivo expansion of CB-derived T cells genetically modified to express CD19 or CD20 chimeric antigen receptors (CARs) to prevent relapse and the ex vivo generation of increased numbers of CB-derived NK cells as a means of better disease control are discussed below. This review focuses on these primary areas of graft engineering, but by no means represents an exhaustive list of the active research ongoing in the field of CB graft engineering. Other areas not covered in this review include the generation of regulatory T cells for GVHD prophylaxis, biological-based bioengineering approaches to enhance stem cell expansion, and preclinical research into the generation of CB-derived induced pluripotent stem cells. With continued advancement in the field, it is possible that a single CB unit could be manipulated based on an individual patient's greatest clinical need, with generation of specific cell types as clinically appropriate (Figure 1). Open in a separate window Figure 1 The potential of CB graft engineering.