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INTRODUCTION
The first cord blood transplantation was performed success- fully in October 1988. 1 This clinical effort was initiated based on a basic science study coordinated by the author’s labora- tory that suggested umbilical cord blood as a potential source of transplantable hematopoietic stem and progenitor cells. 2 The clinical study, which demonstrated hematopoietic recon- stitution in a patient with Fanconi anemia by using human leukocyte antigen (HLA)-identical sibling cells, served as the first proof-of-principal for the initiating scientific study, 2 and as a precursor to the more than 6000 umbilical/placen- tal cord blood transplants performed to the present for a wide variety of malignant and nonmalignant disorders that required a hematopoietic stem cell transplant for treatment and cure. Similarly, the author’s laboratory served as the first cord blood bank that stored the cord bloods used for the first five cord blood transplants performed as well as for two of the second five done.2– Both the laboratory 2 and clinical^1 studies were the result of a multi-institutional national study in the United States, 2 which then opened up into a multi-institutional interna- tional study between investigators in the United States and in Paris, France.^1 The background leading to both efforts has been reviewed in a number of articles. 3–6^ At first, the clinical cord blood transplants were limited to HLA-matched sibling donor cord bloods, with the recipients being children. 7 These encouraging results led to the use of HLA-partially matched transplants in children and then the use of unrelated cord blood transplants that were completely and then subse- quently partially matched for HLA.8–13^ However, because of the limiting number of cells that one can collect from the cord blood at the birth of the baby and the need for greater numbers of cells the larger the recipient’s body weight, rela- tively fewer cord blood transplants have been performed in adults than in children and lower-weight individuals. 11,14– This is changing as transplanters have become more com- fortable with the use of cord blood as a source of transplant- able cells and as clinical understanding and efforts have better developed. 18–
CORD BLOOD TRANSPLANTS IN ADULTS
Although the number of cord blood transplants in adults is still relatively low compared with that for children, these numbers are increasing. 11,14–24^ The recent article by Laughlin and colleagues 19 compared results of 150 patients being
transplanted with cord blood mismatched for one or two antigens, in comparison to 367 matched and 83 one-antigen- mismatched bone marrow transplants. Overall, the recipi- ents of the cord blood transplants were younger, and they were more likely to manifest advanced leukemia than were the recipients of bone marrow transplantation. Moreover, because of the limiting numbers of cells in cord blood com- pared with bone marrow collections, the recipients of cord blood transplants received a lower dose of nucleated cells. For as yet unknown reasons, which may not entirely relate to the dose of nucleated cells infused, neutrophil and plate- let recovery was slower with transplantation of mismatched bone marrow and cord blood, than with matched marrow transplantation. This delayed engraftment with cord blood has been noted since the first cord blood transplant 1 and may relate to the relatively immature nature of cord blood cells. Interestingly, acute graft-versus-host disease (GVHD) was more likely to occur after mismatched marrow transplanta- tion, but chronic GVHD was more evident after cord-blood transplantation. Recipients of mismatched bone marrow or cord blood transplants were similar in treatment-related mortality, treatment failure, and overall mortality, with no differences in the rate of relapse of leukemia. Although the authors noted infections being more prevalent with cord blood, the types of infections did not differ among the three comparison groups. An article by Rocha and associates 20 in the same issue of the New England Journal of Medicine as that of Laughlin and colleagues 19 evaluated outcomes in 682 adults with acute leukemia. Ninety-eight were recipients of cord blood transplantation, and 584 received bone mar- row. This effort was confined to those transplants performed from 1998 to 2002. 20 The cord blood transplant recipients were younger, weighed less, and had more-advanced disease than bone marrow recipients at the time of transplanta- tion. The authors reported lower risks of grade 2 to 4 acute GVHD, but significant delays in neutrophil recovery with cord blood. However, incidence of chronic GVHD, trans- plant-related mortality, relapse, and leukemia-free survival were not significantly different in the two groups. Attempts to reconcile the data 25 in these two articles19,20^ pointed to several possibilities in the two studies that might explain some of the differences noted. The article by Laughlin and colleagues 19 encompassed patients given transplants over a longer period than that of Rocha and associates 20 when the relevance of nucleated cell dose and HLA matching had not yet been fully appreciated. By restricting their analysis to after 1998, Roche and associates 20 likely had better patient and cord blood unit selectivity based on identification of
Hal E. Broxmeyer
Chapter 59
Umbilical Cord Blood Stem Cells:
Collection, Processing, and Transplantation
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potential reasons for better patient outcomes. 22 A prospec- tive study published by the Cord Blood Transplantation (COBLT) study group, supported in part by the U.S. National Institutes of Health, reported somewhat less-favorable results for cord blood transplantation in adults. 23 The primary end point of this study 23 was survival at 6 months, with second- ary end points analyzing engraftment, GVHD, relapse, and longer-term survival. Enrollment into the program required a cord blood collection that contained more than 10^7 nucle- ated cells per kilogram recipient body weight with equal to or greater than four HLA-A and -B (low or intermediate resolution) and -DRB1 (high resolution) matches. Patients included those with acute and chronic myelogenous leuke- mia and acute lymphoblastic leukemia, as well as myelodys- plastic syndrome, paroxysmal nocturnal hemoglobinuria, and non-Hodgkin’s lymphoma. Of these patients, 94% were considered poor-risk candidates by criteria put forth by the National Marrow Donor Program (NMDP). The overall conclusion of the COBLT study^23 was that cord blood trans- plantation should continue to be performed in specialized centers with a research focus on cord blood cells because of the high treatment-related mortality and slow engraftment kinetics they noted. The less-favorable results noted by the COBLT study, 23 compared with that of the results of the arti- cles reported earlier, 19,20^ may in part reflect the much greater poor-risk patients studied in the COBLT study, even though the study was open to both good- and poor-risk patients, as defined by the NMDP. A comparative analysis of the major clinical studies for cord blood transplantation for adults was reviewed by Chao. 26 Most cord blood transplants have been performed by using myeloablative conditioning regimens for the recipients, how- ever, some patients have undergone nonmyeloablative condi- tioning,27,28^ and these have also been summarized by Chao.^26
CURRENT AND FUTURE EFFORTS TO
EXTEND THE REACH OF CORD BLOOD
TRANSPLANTATION TO MORE PATIENTS
Although many unanswered questions remain regarding how to best broaden the applicability of cord blood transplanta- tion, a major effort has gone into trying to adapt cord blood for more-efficient use in adults and high-weight individuals. Limits in the numbers of cord blood cells available in the individual collections of cord blood at the births of babies are clearly a major limiting factor in successful transplantation into adults and high-weight individuals. Current clinical practice uses in the range of greater than or equal to about 2 × 10^7 nucleated cells per kilogram recipient body weight. Whereas this is about a log lower than that recommended for bone marrow trans- plantation, this is compensated for in part by the increased fre- quency and quality of hematopoietic stem and progenitor cells found in the cord blood compared with bone marrow.2,29– However, even being able to generate equal to or greater than 2 × 10^7 nucleated cells per kilogram body weight from single cord blood collections to use in adults is problematic on a routine basis. Attempts to compensate for limiting numbers of nucleated cells in single cord blood collections include (1) use of multiple cord blood units for transplantation into single recipients, (2) ex vivo expansion of single cord blood units, and (3) enhanced quality of the hematopoietic stem and progenitor cells for homing to and engraftment in the appro- priate microenvironment niches of recipient bone marrow.
Use of Multiple Cord Blood Units for
Transplantation into Single Recipients
This mode of using multiple cord blood units for potential transplantation is not new in concept^39 but has only recently demonstrated possible efficacy. 40 Barker and coworkers^40 evaluated the safety of combining two partially HLA cord blood units for transplantation after myeloablative condi- tioning in 23 patients manifesting high-risk hematologic malignancy. Of the 21 evaluable patients, all engrafted at 15 to 41 days, with a median time to engraftment of 23 days. Of interest, and not yet fully understood, engraftment was seen at 21 days for 24% of the patients with both cord bloods, and with only one cord blood in the rest of the recipients. However, only one unit predominated at 100 days in all the patients. The mystery is not only why only one cord blood unit eventually predominated, but also how to predict which of 2 units will predominate. This information would be of great interest, especially in the context of a number of clini- cal trials evaluating an ex vivo expanded cord blood unit in combination with an unmanipulated unit. If only one unit predominates, and it is not clear which unit will “win out,” combining a manipulated cord blood unit (e.g., one that is “expanded” ex vivo) with an unmanipulated cord blood unit may make it extremely difficult to interpret the results. Thus far, neither nucleated nor CD34+ cell doses nor HLA-type of the cord blood collections is predictive of predominance in the host, and CD3+ T-cell dose, which was originally sug- gested as a possible criterion for predominance,^40 has not been substantiated. Many centers are currently using two or more cord blood units for transplantation, although a controlled clinical trial has not yet been performed to prove definitively that the transplantation of more than one cord blood unit is any more efficacious than that of a single unit.
Ex Vivo Expansion of Single
Cord Blood Units
Hematopoietic stem cells are defined by their capacity to self-renew. Being able to harness the self-renewal capacity of these stem cells ex vivo would likely open up the possi- bility for more-consistent use of cord blood transplantation for adults. Also, it is possible that a single collection of cord blood, if effectively expanded in the context of functional stem cells, could be used for engraftment and repopulation of the blood cell system for multiple recipients. Harnessing self-renewal capacity for production/expansion of stem cells is clear for murine stem cells. Unfortunately, it is not apparent that anyone has been able truly ex vivo to expand human hematopoietic stem cells. Without question, ex vivo expansion of hematopoietic progenitor cells is possible, but progenitors do not have the capacity to provide the long- term engraftment needed for successful transplantation. Progenitors may to some extent provide short-term engraft- ment, and it is possible that this may be of some value when expanded progenitors or short-term repopulating stem cells are combined with unmanipulated cord blood units that themselves do not have a high enough nucleated cell content to guarantee long-term engraftment. The expanded progeni- tors may allow the long-term repopulating cells in the unma- nipulated cord blood unit the opportunity to “take hold” and repopulate over the long term in the recipient. Several clinical attempts to use ex vivo expanded cells41, have not provided encouraging results, although efforts in
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exist with the freezing process, the storage, and the defrosting protocol. In actual experimental terms, cord blood cells have been stored at least up to 15 years without loss of functional hematopoietic stem and progenitor cell activity. 2,29,79,80^ In the most recent study from the author’s laboratory to evaluate cord blood cryopreservation, 80 highly efficient recovery was noted for granulocyte-macrophage (CFU-GM), erythroid (BFU-E), and multipotential (CFU-GEMM) progenitor cells in terms of numbers and proliferative capacity of these progenitor cells in vitro after 15 years of storage. Moreover, the recovered CD34+ population of stem/progenitor cells showed more than 250-fold ex vivo expansion of progenitor cells, and the CD34+ cells isolated after defrosting of the cord blood were able to engraft sublethally irradiated NOD/SCID mice with a frequency that was equivalent to that of freshly isolated cord blood CD34+ cells. The author’s laboratory, as of the date of this writing, has cord blood cells frozen for as long as 18 to 19 years and will be able to continue to evaluate the efficacy of recovery of cryopreserved cord blood stem/ progenitor cells stored over the long term. However, others continue to define more-effective cryopreservation methods for cord blood stem/progenitor cells. 81
Cord Blood Banking
In general terms, currently two types of cord blood banks are available. There are those that store cord blood for autolo- gous or related use. These are termed “Private” banks and usually charge an upfront fee as well as a continuing main- tenance fee. Once entered into a contractual agreement with the cord blood banking company, the individual that signed the contract and/or the donor of the cord blood essentially own the blood. The other type of cord blood bank is gener- ally called a “Public Bank.” Once donated to a “Public Bank,” the cord blood is no longer owned by the donor or family of the donor and is available for use, for a fee, by one who is in need of a cord blood stem cell transplant. Cord blood banking has a number of benefits, 82 which include (1) rapid availability of cord blood when needed, as the blood is stored in banks and has been HLA-typed and assessed for the pos- sibility of infectious agents; (2) no donor risk or attrition, as collection of the cord blood is essentially an easy and safe process in the hands of experienced personnel, and can theo- retically be replenished from the multitude of births every day. In contrast to registries such as the National Marrow Donor Program (NMDP) for bone marrow, the cord blood is already present, whereas when the bone marrow is needed, those who signed up to donate the marrow have to be tracked down to see if they can be found and are still willing to donate the marrow, which is obtained through an invasive although relatively safe procedure; and (3) the potential for increasing the pool of donor stem cells for ethnic and racial minorities. In addition, cord blood use opens up the prob- ability for a lower risk of transmitting infectious diseases and appears to manifest a reduced risk of GVHD, as mismatched cord blood appears to elicit less GVHD than does mis- matched bone marrow. The first operational “Public” cord blood banks were established in 1993 in New York, Milan, and Dusseldorf. 82 In 2001, a number of selected organiza- tions were available to ensure quality and standards in cord blood banking,^82 and these included in alphabetical order: American Association of Blood Banks, American Red Cross, Bone Marrow Donors World, Cord Blood Transplantation Study, European Blood and Marrow Transplant Group
(EBMT), Eurocord, Foundation for the Accreditation of Hematopoietic Cell Therapy, Group for the Collection and Expansion of Hematopoietic Cells, International Society for Hemototherapy and Graft Engineering (ISHAGE), Joint Accreditation Committee of ISHAGE-Europe and EBMT, Netcord, and National Marrow Donor Program. Many of these organizations are still available today. Techniques have been developed and continue to be refined efficiently and safely to select donors and to collect, store, process, and distribute cord blood units to areas of need throughout the world. 82 A recent review on new trends in umbilical cord blood transplantation,^83 cited a 2003 reference that listed about 150,000 available cord bloods from 35 different cord blood banks in 21 countries, almost all of which were typed for HLA-A, -B, and -DR, with 76% of the units typed by molec- ular analysis for major histocompatibility complex (MHC) class II antigens, and 49% molecularly typed for MHC class I antigens. These numbers of stored cord blood are now likely an underestimate of those cord blood units available. It was noted that most Cord Blood Banks in the United States operate under an Investigational New Drug (IND) application from the Food and Drug Administration (FDA), as well as an Institutional Review Board (IRB)-approved research consent. 83 Efforts are also still needed to define the best application of cord blood transplantation in the trans- plant donor-choice algorithm,^83 which currently involves a decision between use of mobilized peripheral blood, bone marrow, and cord blood as sources of transplantable and long-term engrafting stem cells.
Report from the Institute of Medicine of the
National Academies of Science, U.S.A.
It was noted that the increase in numbers of cord blood banks in the United States raised a number of important questions,^84 including adequacy of cord blood inventories, standardization of collecting cord bloods, as well as their processing, storage, documentation, and quality control. Moreover, the lack of a single outcomes database has been thought to block the ability of the scientific community to determine best-practice guidelines. Because of these con- cerns, the U.S. Congress provided money, under a 2004 appropriations bill of the U.S. Department of Health and Human Services, to establish a U.S. National Cord Blood Bank Program under the leadership of the Health Resources and Services Administration. The Institute of Medicine report was broken down into questions and recommendations. 84 Among the questions considered, the most specific were (1) What is the role of cord blood in hematopoietic progenitor cell (Author’s note: this should have read hematopoietic stem cell) transplan- tation in the context of other sources of progenitor cells? (2)What is the current status of cord blood banks? (3) What is the optimal structure for the cord blood program? (4) What is the current use and utility of cord blood collections for stem cell transplants? (5) What standards should be set for storage, collection, information sharing, distribution, and outcome measures? (6) What is the best way to make cord blood units available for research? (7) What consent procedures are needed for both the research and transplan- tation use of cord blood? and (8) Should the cord blood pro- gram set practice guidelines for both “Public” and “Private” banks? It was recommended that a national program should
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have as its primary mission the goal of maximizing access to high-quality cord blood units for patient care and research in the most efficient, cost-effective, and ethical manner.^84 This program needed to avoid duplication of efforts in services provided and the steps necessary for a transplant center to access appropriate sources of grafts, with promotion of the best possible chance for patient recovery through the estab- lishment of high-quality, HLA-diverse cord blood units, and an integral part of the program should be support and edu- cation for all individuals involved. It was emphasized that a barrier to the goal of unimpeded access to treatment was the lack of sufficient ethnic and racial diversity in existing stored cord blood units. Specific recommendations for banks and banking included 84 (1) identify a cord blood accrediting organization; (2) establish uniform standards for cord blood collection; (3) establish uniform quality-assurance systems; (4) estab- lish FDA licensure of cord blood units; and (5) apply quality standards to all banks. Specific recommendations for ethical and legal issues included 84 (1) cord blood centers need policies regarding who must provide consent; (2) informed consent should be obtained before the labor and delivery; (3) donors must be provided with clear information about their options (Author’s note: This of course is not possible for cord blood donors but would likely fall up front to the parents of the baby); (4) promote the security of medical informa- tion; (5) cord blood donors must understand the limits of their rights (Author’s note: Again, this is not possible for the baby). The key functions of a National Cord Blood Program were^84 governance, database, unit selections, source of transplanted material, finances, cord blood bank selection, standards, and outcomes data. Although the Institute of Medicine report 84 is clearly a step in the right direction, it may be some time before the differ- ing groups in cord blood banking come to any consensus and the recommendations of the report are implemented.
CORD BLOOD CHARACTERISTICS
Cord blood contains, among a number of cell types, hematopoietic stem and progenitor cells, which are very rare in the total population; and more mature blood cells including B and T lymphocytes, natural killer cells, den- dritic cells, monocytes, and granulocytes. It also contains endothelial progenitor cells and mesenchymal stem cells, the latter giving rise to a number of different cell types other than blood cells. Recent reviews are available on cord blood immune cells. 85–88^ This chapter covers hema- topoietic stem and progenitor cells, endothelial progenitor cells, and mesenchymal stem cells. Table 59–1 lists a brief description of these cells, but this table is not meant to be an all-encompassing assessment of knowledge about these cells. Information on many of these cells, especially those that are not hematopoietic stem and progenitor cells, is still lacking but we hope will emerge soon. Because the author is not clear how these different cells, other than those of hematopoietic stem and progenitor cells, relate to each other in terms of ontogeny and parent-progeny rela- tions, no effort has been made to describe the ontogeny and relations of these apparently different cells to each other.
Hematopoietic Stem and Progenitor Cells
In this group of cells, most is known about hematopoietic progenitor cells in terms of their frequency and proliferative characteristics. Overall, these cells in cord blood appear to have a high quality in terms of their capacity to give rise to progeny and replate in vitro. 2,29–34^ These cells are found in the CD34+ and mainly in the subset of CD34+ CD38+ cells. They can be highly enriched in the CD34+++ population, those CD34+ cells expressing the highest-density distribu- tion of cell surface CD34 antigens. Given the right separa- tion procedure, functional hematopoietic progenitors, as determined by in vitro colony assessment in the presence of combinations of colony-stimulating factors (CSF), such as granulocyte-macrophage CSF, interleukin-3, and eryth- ropoietin, and potent costimulating factors such as stem cell factor and Flt3-ligand, can be found at a frequency of up to 80% in the CD34+++ preparations of sorted cells. Hematopoietic stem cells are functionally assessed by their capacity to repopulate the bone marrow of sublethally irra- diated NOD/SCID mice 35–37,78^ and are highly enriched in the CD34+ CD38− population of cells, but only 1 in about 700 CD34+CD38− cord blood cells is a NOD/SC1D repopulat- ing cell (SRC). This frequency is much greater than that for SRC in bone marrow or mobilized peripheral blood. Genomic89–93^ and proteomic^94 profiling of hematopoietic stem and progenitor cells has been reported, and future stud- ies could shed light on profiles of stem cells and progeni- tor cells. However, current genomic and proteomic analysis of hematopoietic stem and progenitor cells is only as good as the methods used and the cell populations analyzed. As noted earlier, even phenotypically isolated human cord blood hematopoietic progenitor cell populations are not pure, and the best separations for human cord blood SRC only yield a preparation in which the hematopoietic stem cell population is present in rare frequency. Thus information obtained on the genomics and proteomics of human hematopoietic stem and progenitor cells has to be interpreted with caution.
Endothelial Progenitor Cells
Progenitors for endothelial cells are present in human cord blood, 95–105^ and an hierarchy of cells within the endothelial progenitor cell population has been identified, 103 based on their clonogenicity and proliferative potential. The high- proliferative-potential endothelial progenitor cell achieved at least 100 population doublings and could be replated to form colonies in secondary and tertiary dishes with main- tenance of high telomerase activity. Of interest, endothelial progenitor cells from cord blood had much greater prolifera- tive potential than those found in adults.^103
Cells with Differentiating Capacity for More
than Blood Cells
Stem cells in various organs do not always meet the same definition rigor. This was especially apparent in recent dis- cussions on the topic.106,107^ The most rigorous definition of stem cells is that for hematopoietic stem cells, which should serve as the paradigm for stem cells of all organs, but agree- ment on this is far from unanimous.^106 Mesenchymal stem cells are reported to produce bone, fat, and cartilage, and this multipotentiality may be the best reason for considering a mesenchmyal stem cell to be a stem
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cell. However, in most cases, these cells are poorly defined by both phenotypic markers and functional activity as actually being stem cells, at least as assessed by single isolated cells giving rise to all different tissue types. 108 Lack of evidence exists for self-renewal capacity, although their proliferative potential is not in question. Mesenchymal stem cells are found in a number of tis- sues, including cord blood. 108–115^ However, not all reports have shown these cells to be present in cord blood, and great variability is found in detection of the frequency of these cells in different cord blood collections, even when they are found. 116–118^ This could be a technical problem of detection or may truly reflect variability in presence of mesenchymal stem cells in cord blood. Such variability and their low frequency in some cord bloods may dampen the potential therapeutic usefulness of these cells, making it difficult to translate the use of these cells into clinical application. Cryopreservation of mesenchymal stem cells has been reported. 119 Multipotent adult progenitor cells (MAPCs), which are reported to differentiate into endothelial, epithelial, and mesenchymal cells, have been detected in bone marrow,120– but not in cord blood. 125 However, an unrestricted somatic stem cell (USSC) population has been reported to be pres- ent in cord blood.^126 USSCs are CD45− and MHC class II antigen− cells, which are found in only 40% of cord blood collections (94 of 233) analyzed, and even when found, are extremely rare. In contrast to mesenchymal stem cells, the USSCs were purported to be able to differentiate into osteo- blasts, chondroblasts, adipocytes, and hematopoietic and neural cells, including astrocytes and neurons.^126 They were reported to differentiate along mesodermal and endodermal pathways in vivo. 126 More information on USSCs will need to be forthcoming from the group that published the original article on this cell,^126 as well as verification from the other groups, before the true value and ramifications of its clinical relevance are appreciated. Plasticity of stem cells, the ability of one cell to give rise to numerous cells of different tissues, is still a controversial issue, in no small part due to the lack of rigor described for the experiments performed. Moreover, other potential pos- sibilities exist for the purported plasticity, including cell fusions and the presence of separate progenitor cells in the population, rather than one stem cell population giving rise to the different tissue types. Recent reviews and original scientific papers have discussed the issue of plasticity. 127– Because of the ill-defined surface characteristics of mesen- chymal stem cells, it is also unclear how multipotential these cells are, and if indeed attributes associated with these cells are actually due to one cell or to a number of different cells in the population.
CONCLUDING REMARKS
Ongoing studies will delineate which cell in cord blood has what functional property and differentiation capacity and should allow us to determine whether cord blood cells can be used in cellular therapy and regenerative medicine for more than replenishment and correction of the blood cell system. It is clear that more rigorous information on the properties of the cells present in cord blood will help not only to define their ontogeny, but also further to broaden therapeutic applications of these cells.
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