Making a little go a long way…

In this issue of Blood, Popat et al report the results of a clinical trial designed to test the safety and feasibility of a novel strategy, enforced fucosylation, intended to improve engraftment after donor unrelated cord blood (UCB) transplantation in adults. The data show that the strategy is safe, and that engraftment of platelets and neutrophils is faster in recipients of the modified cord blood (CB) unit when compared with historical controls.¹ 

The first successful UCB transplant was reported in 1989. Gluckman et al transplanted sibling donor UCB into a child with Fanconi anemia, and demonstrated full and durable engraftment.²  This ground-breaking report was followed by additional reports of sibling donor UCB transplants, and subsequently, the development of unrelated donor umbilical CB banks, expanding the strategy to children without stored HLA-matched sibling donor UCB units, a relatively infrequent clinical scenario.³  Studies in children demonstrated important advantages of UCB grafts, including an ∼50% reduction in risk of acute graft-versus-host disease (GVHD) and a low frequency of chronic GVHD. Relative tolerance of HLA mismatch allows the use of UCB units with greater mismatch than is tolerable with an adult graft.^4,5  Moreover, use of a frozen graft allows scheduling the date of transplant around the recipient’s clinical condition, without concerns for donor convenience and scheduling of stem cell collections. The importance of cell dose in determining outcome of UCB transplant became evident in pediatric studies, and UCB bankers now focus on collection of the largest units possible. Despite this, cell dose limitations largely confined use of UCB transplantation to smaller children.

Successful UCB transplantation in adults clearly requires the acquisition of more stem cells than are in a typical UCB graft, or improvement in the ability of the available stem cells to engraft. A simple approach to increasing the number of available stem cells is to use 2 UCB units instead of 1. This strategy has been pioneered by investigators at the University of Minnesota, and has been shown to be effective in achieving engraftment, albeit with significant frequency of acute GVHD, but possibly with a reduced rate of relapse, at least in some adult studies.^6,7  An alternative strategy to double CB transplantation is ex vivo expansion of stem cells from a single CB unit, as shown by Horwitz et al.⁸  Expanding stem cells while maintaining the self-renewal capacity of stem cells has proved challenging. Expansion strategies have included coculture with mesenchymal stem cells, immobilized notch ligand, copper chelation, and culture with nicotinamide. Each of these approaches is in multicenter trials, but none is as yet an established therapy. A second alternative to double CB transplant is exposure of the graft to compounds aimed at improving the engraftment potential of the stem cell, either by improving homing, engraftment, or proliferation. Exposure to a small molecule, StemRegenin, has been shown to promote the expansion of CD34⁺ cells, and early clinical trials are in progress.⁹  Additionally, a phase 1 clinical trial of double CB transplantation in which one unit has been incubated for 2 hours with a stable derivative of prostaglandin E₂ showed improved engraftment. A phase 2 study is currently under way.¹⁰ 

A different approach to improve engraftment of UCB is reported by Popat et al.¹  Delayed engraftment of UCB cells may be due, at least in part, to poor homing to the bone marrow (BM), due to the relatively weak affinity of many UCB CD34⁺ cells for the BM microvasculature. This deficit appears to be due to reduced levels of fucosylation of E- and P-selectin ligands on UCB cells compared with those on marrow or peripheral blood stem cells. Popat et al hypothesized that increasing the level of CD34⁺ cell surface fucosylation ex vivo could improve hematopoietic stem and progenitor cell (HSPC) homing to the marrow in transplant recipients and enhance engraftment of neutrophils and platelets. The authors tested this hypothesis in a first-in-man clinical trial. The study included adults with hematologic malignancies receiving a double UCB transplant. Units were matched with recipients with at least 4 HLA loci, and each unit had a cell dose of at least 1.5 × 10⁷ total nucleated cells per kilo of recipient weight. The larger of the 2 CB units was infused without manipulation. The smaller of the UCB units was treated ex vivo for 30 minutes with the enzyme fucosyltransferase VI and guanosine diphosphate fucose to enforce fucosylation of the HSPC. The clinical trial demonstrated more rapid recovery of neutrophils and platelets in recipients of fucosylated UCB units than in historical controls, and no unexpected toxicities were attributable to the fucosylation. Chimerism studies showed that the unfucosylated unit dominated in about half the transplants, a surprising finding because the authors expected more rapid engraftment to be due to recovery of the fucosylated unit and therefore expected dominance of the manipulated unit. It is possible that the chimerism was transient and measurements were made too late, or that the fucosylated unit served to facilitate engraftment of the fucosylated and nonfucosylated HSPCs.

This study represents an important advancement in the field of UCB transplant. The strategy used is appealing because it is simple and could be performed in any institution with a cell manipulation laboratory. Previous cell expansion studies have shown similar improvements in engraftment but require complex and time-consuming manipulations in a good manufacturing practice facility. More rapid engraftment will be expected to reduce later infections, and perhaps reduce mortality, but these key end points require a larger study.

Although an important advancement, this is an early-phase study of 22 patients, so future larger randomized studies will be needed to confirm these results in a larger data set and explore the mechanism of enhancement of engraftment. The technology use in this strategy appears simpler and more suited to a multicenter study than many approaches to improving engraftment.