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Umbilical cord cell banking—implications for the future
Toxicology and Applied Pharmacology 207 (2005) S538 – S543 www.elsevier.com/locate/ytaap
Review
Umbilical cord cell banking—implications for the future Jennifer Gunning* Cardiff Law School, Cardiff University, Law Building, Museum Avenue, Cardiff CF10 3XJ, UK Received 12 July 2004; revised 21 January 2005; accepted 21 January 2005 Available online 27 June 2005
Abstract The first successful cord cell transplant to a sibling with Fanconi’s anaemia took place 15 years ago. This proven utility of cord blood led to the establishment of cord blood banks both private and public and there are now nearly 100 cord blood banks worldwide. It is estimated that over 200,000 cord blood units (CBU) are held by the private sector and over 160,000 CBU are registered with the largest public cord blood registry. There is a tension between private cord blood banks, which store CBU for autologous or family use, and public banks, which store CBU for unrelated use and the ethics of private cord blood storage has been questioned. But more general ethical questions also arise regarding ownership, consent, confidentiality, costs and quality standards and patenting. In looking at these ethical issues one also needs to look at potential future use of cord blood stem cells. Up until now cord cells have principally been used in the treatment of paediatric blood and immune disorders. Improvements in cell expansion technology will make CBU more appropriate also for treating adults with such disorders. However, it has also been demonstrated that cord blood stem cells have the capacity to differentiate into other types of cells, neuronal, bone, epithelial and muscle which would have a future role to play in cell therapy and regenerative medicine. D 2005 Elsevier Inc. All rights reserved. Keywords: Cord blood; Stem cells; Tissue banking
Contents Advantages and disadvantages of using cord blood Advantages . . . . . . . . . . . . . . . . . . . Disadvantages . . . . . . . . . . . . . . . . . The current status of cord cell banking . . . . . . Current and future use of umbilical cord cells . . . Conclusion . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . .
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The first successful cord cell transplant to a sibling with Fanconi’s anaemia took place in 1988 (Gluckman et al., 1989). This proven utility of cord blood led to the establishment of cord blood banks. The first private and public banks were established in 1992. There are now some 100 cord blood banks worldwide. * Fax: +44 29 208 74097. E-mail address: [email protected].
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Historically bone marrow transplantation has been used in the treatment of patients with blood and immune disorders requiring a source of haematopoietic stem cells (HSC). Until recently, the blood remaining in the placenta and umbilical cord following the birth of a baby was discarded as a waste product. However, it has been determined that umbilical cord blood is some ten times richer than bone marrow in its proportion of progenitors of haematopoietic stem cells (Broxmeyer et al., 1990). More-
0041-008X/$ - see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.taap.2005.01.027
YTAAP-10287; No. of pages: 6; 4C:
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over, lymphocytes in cord blood appear to be less immunologically active than those found in bone marrow (Cohen and Madrigal, 1998) and the incidence of graft versus host disease (GVHD) lower. These factors make cord blood an attractive alternative to bone marrow for a number of conditions and, following the report of the 1988 case, cord blood banks were established first in the United States and Europe and now there are many such banks worldwide both in the public and private sectors. Early transplants were to siblings but with the establishment of public cord blood banks unrelated cord cell transplants were enabled first in children and then, to a lesser extent, in adults.
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& Cord blood units do not have to be a perfect HLA match because of the reduced incidence of GVHD. This means that it is possible to use unrelated and mismatched donors (Gluckman et al., 1997; Wagner et al., 1996). While sibling donors were used in early cord blood transplants, the establishment of cord blood banks means that it has been possible increasingly to use unrelated donors. & The risk of transmission of infectious disease is diminished for cord blood because all CBU are screened for disease and any infected or contaminated units discarded. Disadvantages
Advantages and disadvantages of using cord blood Advantages & Cord blood units (CBU) are more rapidly available than bone marrow. Bone marrow is obtained from volunteer donors who are recruited by blood and transplantation services and other organisations. Donor details, including ethnicity, HLA and blood type, are held in registers. If a transplant is needed by a patient, their clinician will search the bone marrow registries for a match. The volunteer will then be approached for a bone marrow donation and tests for disease and other exclusion criteria will be carried out. This process is time consuming and it may take many weeks before a suitable donation becomes available, if at all, for the critically ill patient. There is always a risk that the volunteer will change their mind about donating. Cord blood units are stored frozen after thorough testing for contamination and specified diseases, such as hepatitis B and C and HIV, and there is no risk of last minute consent refusal. & Cord blood is less risky to collect. The collection of cord blood following delivery is a harmless process that does not affect the mother or her newborn. Cord blood can, therefore, be collected at no risk to the donor and stored, frozen, until needed. The harvesting of bone marrow is an invasive process that can cause some risk and discomfort to the donor. Bone marrow is therefore not collected until it is needed. & The number of potential donors is high. Recruitment of cord blood donors from antenatal clinics is relatively easy and only a very small number of women, from amongst those who might be willing to donate, is ever approached. Potential bone marrow donors are not so readily identifiable although many will be blood donors. & There is a decreased risk of GVHD. The cells in cord blood appear to be more Fnaive_ than their counterparts in bone marrow because of the immune immaturity of the newborn. It has also been shown been shown that the low number or absence of CD8+ natural killer (NK) T cells in cord blood may also be a relevant factor (Kim and Broxmeyer, 1996).
& The time to platelet engraftment is prolonged in the transplantation of cord blood in comparison to bone marrow (Rubinstein et al., 1998). This study also showed that engraftment time was strongly related to cell dose. & The cell dose of CBU is generally insufficient for adults. Although cord blood is enriched in haematopoietic stem cells (HSC) its volume is less than is collected from bone marrow. This makes CBU more suited to paediatric use. Clinical experience has shown that to successfully treat an adult the nucleated cell dose in the CBU must be at least 1.5 –2.0 107/kg body weight (Ballen et al., 2001; Gluckman et al., 1998), and it has been shown that a cord blood nucleated cell dose of 0.37 108/kilo increased the speed and probability of engraftment (E. Gluckman, personal communication). The Du¨sseldorf NetCord bank has had a policy of collecting only units larger than 80 ml since 1997. In these units the median number of nucleated cells was 10 T 5 108/U and only 25% of the units contained enough cells to engraft patients of 50– 70 kg. To overcome this problem multiple units of cord blood have been transplanted but usually only one CBU engrafts. Cord blood has a higher potential for in vitro proliferation than adult bone marrow (Piacibello et al., 1997), and currently a considerable body of research is being undertaken into cell expansion to overcome the cell dose problem. Most of this research is being validated in mouse models (Encabo et al., 2003; Ohishi et al., 2002) but some expanded units have already been used in the human clinical context as part of a trial (Jaroscak et al., 2003; Pecora et al., 2000). Eurocord III, funded by the EU under the Cell Factory area of FP5, will carry out an evaluation of umbilical cord blood transplant engraftment using ex vivo haematopoietic progenitors/stem cell expansion. The study will collect and compare techniques of ex vivo stem cell expansion; interact with biotechnology companies to procure cytokines and other reagents for clinical use; and compare pre-clinical animal models in mice and sheep and then design clinical protocols for ex vivo expansion of cord blood stem cells and multiple transplants. The results will be analysed and compared with the Eurocord database registry.
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& There is a risk that hereditary disorders, undiagnosed in the donor at birth, may be transmitted to the recipient.
The current status of cord cell banking Cord blood units (CBU) may be stored in for-profit private banks where parents pay for the storage of their child’s cord blood or in non-profit public banks where parents donate their child’s cord blood for unrelated use. Private banks recruit clients from obstetric clinics, via the Internet and through other promotional material. One American company, BirthCells Technology Inc., provides inducements to recruiters in the form of commission on every Fsale_ and to parents in the form of club membership for the child which gives entry to a sweepstake providing access to four $10,000 college scholarships per year. Cord blood collected for private banks may come from obstetric clinics which are far from their processing and storage facilities. Cord blood units are therefore shipped by courier/delivery service. Although some private banks do provide training materials for obstetric staff undertaking collection, they have no control over collection standards and the obstetricians or midwives collecting CBU for private banking may have little or no experience. Often the collection kits are provided directly to the parents requesting the service and they give them to their obstetrician. The risk of contamination must be higher where those responsible for the collection of cord blood do not carry out the procedure regularly and have little formal training. Although most of the larger private banks have their own processing and storage facilities others make use of Fnonprofit_ facilities. For instance, CorCell Inc., based in Philadelphia, Pennsylvania, uses the processing and storage facilities of the Elie Katz Umbilical Cord Blood Program at Bergen, New Jersey. The Elie Katz Cord Blood Program is a principally non-profit bank and providing services to CorCell Inc. allows it to offset its operating costs. Some private banks, such as the California Cryobank and Cryobanks International, were already established as tissue banks before taking CBU, the former being one of the oldest sperm banks in the United States. Two strategies are used for the collection of cord blood and are common across all types of bank. Cord blood units are collected either in utero, before placental expulsion, or ex utero, following placental expulsion. The former seems to be the preference when collection is undertaken by obstetric staff and the latter favoured by blood services staff. Research does not seem to show any advantage of the one collection method over the other (Lasky et al., 2002; Solves et al., 2003). In utero collection may give better volume at a higher risk of contamination, ex utero collection may compromise volume. Blood can be collected into syringes or into specially designed bags. The collected blood is then processed and screened for contamination and infectious diseases (HIV, hepatitis, etc.) and stored at 196 -C in liquid nitrogen.
There is a tension between private cord blood banks, which store blood for autologous or family use, and public banks, which store blood for unrelated use. There is an inference that private banks are taking out of circulation cord blood units which might otherwise be used for unrelated recipients. It is not clear that this is the case since public banks restrict their collection to a local network of hospitals and it is difficult for women outside their target population to donate. Private banks have no such restrictions. But a recent study found that women in antenatal clinics had very little knowledge about cord blood banking although the great majority of those questioned would have been willing to donate altruistically; only 14% would have elected to bank privately Fernandez et al. (2003). Private cord blood banks currently offer contracts for 18– 20 years storage. Recent research indicates that this may be reasonable as CBU stored for 15 years have been thawed successfully and been able to undergo cell expansion. Engraftment into NOD/SCID mice was comparable to fresh cord blood (Broxmeyer et al., 2003). People using private storage are usually required to pay a non-refundable enrolment fee of about $150 (175), which includes the cost of the collection kit, there will then be the costs of processing the and storing the cord blood unit, following a successful collection, which may bring the cost up to nearly $1,000 (C855). Private banks usually offer prepaid storage deals. In Europe this can range from C1,185 to C1,800 for 20 years of storage. Non-profit or public banks predominate in Europe. They too recruit from obstetric clinics but usually within a local or regional network. They will generally have a policy of collecting CBU from as wide a diversity of ethnic groups as possible and patients wishing to donate cord blood may find difficulty in doing so if they do not come from within the catchment area of a public bank. Collection methods for the CBU are effectively the same as within the private sector and will differ principally as to whether blood collection is undertaken by blood services of obstetric staff. The funding of the non-profit banks comes from a number of sources and in some cases is precarious. Sources of funding in the United States are US Federal Government support through NIH grants, contributions from charitable foundations, support from American Red Cross Biomedical Services or from running parallel private banking services. Red Cross funding also supports public banks elsewhere in the world. The only Canadian public cord cell bank has no secure long-term funding arrangements although it has received Canadian and Provincial government funding in the past and it is now actively soliciting funds from the private sector. In Europe the Jose Carreras Foundation is an important source of charitable funds and other charitable foundations, such as l’Associazone Donatrici Italiane Sangue di Cordone Ombelicale (ADISCO) in Italy, also contribute. The cord cell bank in Milan also receives Regional Government funding. State funding is also provided to
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banks in Australia, Japan, Poland and Spain. In Australia all the public banks have been funded by Commonwealth, States and Territories Governments since 2001. Previously, the banks in Queensland and New South Wales were dependent on research, charitable and community funds and grants. Public banks also receive income from charging the users of CBU and these can be substantial (in Italy sample charges are C17,000 (Bologna) and C17,675 (Milan)). But use is low with only 1 – 3% of units stored being used in any one year while the setting up an maintenance costs are high. Moreover, public banks which supply data to international registries have to undertake sophisticated tissue typing and DNA tests which private banks storing for autologous use do not. Both types of bank would be expected to carry out contamination and communicable disease tests. Private banks pass these processing costs on to their customers. However, tissue typing costs are high and these tests would not routinely be offered by private banks in their storage contracts. Bone Marrow Donors Worldwide, based in Leiden in the Netherlands, is the largest clearing house for cord blood units in public cord cell banks, and in May 2004 it had registered over 167,000 CBU being held in over 18 countries. The number of CBU held in private cord blood banks is unknown but the Cord Blood Registry alone claims to hold nearly 60,000 and Cryo-Cell International over 60,000. The Royal Australia and New Zealand College of Obstetricians and Gynaecologists (RANZCOG) in its 2003 statement on umbilical cord blood banking (RANZCOG, 2003) estimated that 200,000 CBU are held in private banks for autologous use. This has probably considerably increased by now. Outside the United States, there appears to be little knowledge among the public about umbilical cord blood banking. A survey in Canada (Fernandez et al., 2003) has shown that a high proportion (70%) of women attending antenatal classes at a regional hospital had a poor or very poor knowledge of cord blood banking. This is surprising since one might expect them to be actively targeted by private banks in the United States and Canada. Of the 443 respondents to a questionnaire 86% were willing to make altruistic donations of cord blood with only 14% preferring to elect private banking. Research was considered an acceptable use of cord blood by the majority of respondents. It would therefore seem that umbilical cord blood is a largely untapped resource, the logical consequence of which would be to routinely store CBU with women being able to elect private storage if they wished. However, it is likely that the costs of public cord blood banking would mitigate against this. At present, quality standards for the storage of cord blood are mostly ensured through a number of voluntary accreditation schemes and there is little statutory regulation. Recently, the European Directive (2004/23/EC of 31 March 2004) on setting standards for quality and
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safety for the donation, procurement, testing, processing, preservation, storage and distribution of human tissues and cells came into force. This tissue banking directive will apply to all biobanks, including cord cell banks (though not banks storing blood or blood products), in the public sector. Other countries, notably Australia and Germany, impose GMP standards. However, elsewhere standards apply which have been developed by bone marrow transplant organisations or blood services such as the Foundation for the Accreditation of Cellular Therapy and the American Association of Blood Banks. Standards for registries holding details of haematopoietic stem cell donors are set by the World Marrow Donor Association. In the United States the FDA is in the process of drawing up tissue banking regulations and it has been agreed that the Health Resources and Services Administration will put $10,000,000 into funding a National Cord Blood Stem Cell Bank Program but this expenditure will await a report on the issue from the Institute of Medicine. In the meantime there is disagreement between among cord blood banks and registries as to how the program should work (Reed, 2004). In Europe the current mood is principally against private cord cell banking. A recent opinion on the ethical aspects of umbilical cord blood banking (European Group on Ethics, 2004) states that the likelihood of an individual to need an autologous graft of HSC was, at the present time, non-existent and that so far there is no proven utility of other stem cells from cord blood. These would have to meet stringent criteria before they could be used clinically and there was no evidence, if they did, that the subject’s own bone marrow or a well-matched donation from an allogeneic donor would not suffice. The Opinion mentions the draft recommendation of the European Health Committee of the Council of Europe which states, ‘‘the promotion of donation for autologous use should not be supported by member States or their health services.’’ In February 2002 the French National Consultative Ethics Committee, in its Opinion No. 74, warns of private banks that ‘‘. . . setting up such banks is likely to contradict the principle of solidarity, without which no society can survive’’ and that ‘‘Such banks raise hopes of utopia and disguise a mercantile project using assistance to children as a screen.’’ Private cord blood banking is prohibited by law in Italy. In the United States, on the other hand, private cord blood banks have had relatively free rein. However, they are now coming under attack from within the mercantile system itself. The patenting of the processing and storage procedures for cord blood banking in the United States and Europe has threatened cord blood banks with the additional cost of having to operate under license. In April 2003, after a four year legal battle, the European patent was revoked. More recently, the patent holder has successfully pursued a lawsuit for patent infringement against four private cord blood banks in the United States being awarded $7.1
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Table 1 Diseases treated by cord blood transplantation Malignant diseases Acute lymphocytic leukaemia Acute myelocytic leukaemia Chronic myelogeneous leukaemia Juvenile chronic myelogeneous leukaemia Myelodysplastic syndrome Neuroblastoma Non-malignant diseases Adrenoleukodystrophy Amegakaryocytic thrombocytopenia Blackfan – Diamond syndrome Dyskeratosis congenital Fanconi’s anaemia Globoid cell leukodystrophy Gunther disease Hunter syndrome Hurler syndrome Idiopathic aplastic anaemia Kostmann syndrome Lesch – Nyhan syndrome Osteopetrosis Severe combined immune deficiency Thalassaemia X-linked lymphoproliferative syndrome Adapted from Ballen et al., 2001.
million in damages. This judgement is being challenged. Pharmastem is now pursuing another five private cord blood banks.
Current and future use of umbilical cord cells To recapitulate, umbilical cord blood is some ten times richer in haematopoietic stem cells than bone marrow but the volume collected is smaller. Success and speed of engraftment is related to the number of stem cells transplanted. Cord blood has, as a result, been more suitable for paediatric than adult use but advances in cell expansion technology mean that cord blood units may become more suitable for adult use in the future. Until then, cord cell transplants may continue to be regarded as experimental by many physicians. However, in the longer term, the demand for CBU may increase for other reasons. Umbilical cord blood is being used in the treatment of an increasing number of malignant and non-malignant diseases. Table 1 shows the diseases treated by cord blood transplantation so far in some 3500 transplants worldwide. But the focus here is still on haematopoietic stem cells. Recently it has been discovered that cord blood also contains pluripotent stem cells which have the capacity to develop into neuronal, muscle and bone forming cells (Ko¨gler et al., 2004) and into endothelial cells (Bompais et al., 2004; Le Ricousse-Roussanne et al., 2004). It has also been reported that autologous bone marrow cell trans-
plantation has been used successfully in the treatment of patients with severe heart failure (Perin et al., 2003). It is likely that cord blood cells would have similar properties, and in the longer term future, it would seem that stem cells from umbilical cord blood might have a significant role to play in cell therapy and regenerative medicine. It is therefore not surprising to find biotech companies being established alongside cord blood banking facilities. In Europe, Kourion Therapeutics AG was established alongside the non-profit Du¨sseldorf Cord Blood Bank with the director of the Cord Blood Bank as a scientific advisor and on the board of directors of the company. The company, which estimates that the total cell therapy market will amount to more than $30 billion by the end of the decade, is developing cell therapies for the treatment of bone defects and for myocardial regeneration using a proprietary lineage of unrestricted somatic stem cells (USSC) isolated from umbilical cord blood. Kourion Therapeutics has recently been taken over by the American company Viacell, the parent company of the Viacord private cord blood bank. Also in the for profit cord blood banking sector, Cryo-Cell Europe has recently acquired MainGen GmbH, a company located in Frankfurt that specialises in the processing, preparation and expansion of stem cells from cord blood and bone marrow with interests in cell and gene therapy.
Conclusion With the perfection of cell expansion technology, stem cells from umbilical cord blood may well become a preferred option for the treatment of those diseases where bone marrow is currently used. This will also be dependent on reliable, high-quality banking standards worldwide. It is clear that cell therapy could also become a major use for cord blood stem cells in the not too distant future. These cells have the advantage that they are more plentiful and more accessible than adult stem cells and they have already been shown to differentiate into a number of different cell types other than haematopoietic cells. They would be ethically more acceptable than embryonic stem cells. But there are a number of questions that need to be answered. Where should these stem cells be stored? The storage costs of the private sector might look like good value if the potential use of cord cells includes cell therapy and regenerative medicine. But this will limit access to those using private storage. Certainly the routine collection of cord blood from all newborn would overcome the problems of supply and diversity. If this could be publicly funded this would ensure access by all individuals to compatible cells, if not their own. But cost will be a major inhibitor, particularly as current attitudes are skewed towards use only for blood disorders and long-term strategies for the storage of cells for other purposes seem unlikely. Should there be competition between the public and private sectors for such a resource?
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Who should bear the costs? JJ Nietfeld (personal communication) in a recent report to the Netherlands Organisation for Health Research and Development (ZonMw) has suggested that, if cell expansion becomes standardised, where stem cells are stored for personal use part of the cells could be donated for use by third parties (Chapter 5, Section 2.3). He also suggests that banks might obtain extra revenue from the sale of a very small portion (2%) of the stem cells for research. The private sector is already investing in the development of unrestricted somatic stem cells from cord blood for use in cellular therapies and will wish to more than recoup its costs in what it sees as a $30 billion market. In Europe the biggest purchasers will be the national health services treating patients but in countries like the UK such costly therapies may be less widely available in the public sector. The issue of access to these new therapies is a question that needs to be addressed.
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and the European blood and marrow transplantation group. N. Engl. J. Med. 337 (6), 373 – 381. Gluckman, E., Rocha, V., Chastang, C., 1998. Cord blood banking and transplant in Europe. Eurocord. Bone Marrow Transplant. (Suppl. 1), S68 – S74. Jaroscak, J., Goltry, K., Smith, A., Waters-Pick, B., Martin, P.L., Driscoll, T.A., Howrey, R., Chao, N., Douville, J., Burhop, S., Fu, P., Kurtzberg, J., 2003. Augmentation of umbilical cord blood (UCB) transplantation with ex vivo-expanded UCB cells: results of a phase 1 trial using the AastromReplicell System. Blood 101 (12), 5061 – 5067. Kim, Y.J., Broxmeyer, H.E., 1996. CD8+ NKT cells, low in cord blood, preferentially require 4-1BB rather than CD28 for costimulation. Blood (Suppl. 1 pt.1), 240a (abstract 1031). Ko¨gler, G., Sensken, S., Airey, J.A., Trapp, T., Muschen, M., Feldhahn, N., Liedtke, S., Sorg, R.V., Fischer, J., Rosenbaum, C., Greschat, S., Knipper, A., Bender, J., Degistirici, O., Gao, J., Caplan, A.I., Colletti, E.J., Almeida-Porada, G., Muller, H.W., Zanjani, E., Wernet, P., 2004 (Jul 19). A new human somatic stem cell from placental cord blood with intrinsic pluripotent differentiation potential. J. Exp. Med. 200 (2), 123 – 135. Lasky, L.C., Lane, T.A., Miller, J.P., Lindgren, B., Patterson, H.A., Haley, N.R., Ballen, K., 2002. In utero or ex utero cord blood collection: which is better? Transfusion 42 (10), 1261 – 1267. Le Ricousse-Roussanne, S., Barateau, V., Contreres, J.O., Boval, B., Kraus-Berthier, L., Tobelem, G., 2004. Ex vivo differentiated endothelial and smooth muscle cells from human cord blood progenitors home to the angiogenic tumor vasculature. Cardiovasc. Res. 62 (1), 176 – 184. Ohishi, K., Varnum-Finney, B., Bernstein, I.D., 2002. Delta-1 enhances marrow and thymus repopulating ability of human CD34(+)CD38( ) cord blood cells. J. Clin. Invest. 110 (8), 1165 – 1174. Pecora, A.L., Stiff, P., Jennis, A., Goldberg, S., Rosenbluth, R., Price, P., Goltry, K.L., Douville, J., Armstrong, R.D., Smith, A.K., Preti, R.A., 2000. Prompt and durable engraftment in two older adult patients with high risk chronic myelogenous leukemia (CML) using ex vivo expanded and unmanipulated unrelated umbilical cord blood 25 (7), 797 – 799. Perin, E.C., Dohmann, H.F., Borojevic, R., Silva, S.A., Sousa, A.L., Mesquita, C.T., Rossi, M.I., Carvalho, A.C., Dutra, H.S., Dohmann, H.J., Silva, G.V., Belem, L., Vivacqua, R., Rangel, F.O., Esporcatte, R., Geng, Y.J., Vaughn, W.K., Assad, J.A., Mesquita, E.T., Willerson, J.T., 2003. Transendocardial, autologous bone marrow cell transplantation for severe, chronic ischemic heart failure. Circulation 107 (18), 2294 – 2302. Piacibello, W., Sanavio, F., Garetto, L., Severino, A., Bergandi, D., Ferrario, J., Fagioli, F., Berger, M., Aglietta, M., 1997. Extensive amplification and self-renewal of human primitive hematopoietic stem cells from cord blood. Blood 89 (8), 2644 – 2653. RANZCOG, 2003, Umbilical cord cell banking. Statement: No C-Obs. RANZCOG, Australia. Reed, A., 2004. Blood Treatment’s Promise Mired in Bureaucracy. New York Times. (May 29). Rubinstein, P., Carrier, C., Scaradavou, A., Kurtzberg, J., Adamson, J., Migliaccio, A.R., Berkowitz, R.L., Cabbad, M., Dobrila, N.L., Taylor, P.E., Rosenfield, R.E., Stevens, C.E., 1998. Outcomes among 562 recipients of placental-blood transplants from unrelated donors. N. Engl. J. Med. 339 (22), 1565 – 1577. Solves, P., Moraga, R., Saucedo, E., Perales, A., Soler, M.A., Larrea, L., Mirabet, V., Planelles, D., Carbonell-Uberos, F., Monleon, J., Planells, T., Guillen, M., Andres, A., Franco, E., 2003. Comparison between two strategies for umbilical cord blood collection. Bone Marrow Transplant. 31 (4), 269 – 273. Wagner, J.E., Rosenthal, J., Sweetman, R., Shu, X.O., Davies, S.M., Ramsay, N.K., McGlave, P.B., Sender, L., Cairo, M.S., 1996. Successful transplantation of HLA-matched and HLA-mismatched umbilical cord blood from unrelated donors: analysis of engraftment and acute graft-versus-host disease. Blood 88 (3), 795 – 802.
Review
Umbilical cord cell banking—implications for the future Jennifer Gunning* Cardiff Law School, Cardiff University, Law Building, Museum Avenue, Cardiff CF10 3XJ, UK Received 12 July 2004; revised 21 January 2005; accepted 21 January 2005 Available online 27 June 2005
Abstract The first successful cord cell transplant to a sibling with Fanconi’s anaemia took place 15 years ago. This proven utility of cord blood led to the establishment of cord blood banks both private and public and there are now nearly 100 cord blood banks worldwide. It is estimated that over 200,000 cord blood units (CBU) are held by the private sector and over 160,000 CBU are registered with the largest public cord blood registry. There is a tension between private cord blood banks, which store CBU for autologous or family use, and public banks, which store CBU for unrelated use and the ethics of private cord blood storage has been questioned. But more general ethical questions also arise regarding ownership, consent, confidentiality, costs and quality standards and patenting. In looking at these ethical issues one also needs to look at potential future use of cord blood stem cells. Up until now cord cells have principally been used in the treatment of paediatric blood and immune disorders. Improvements in cell expansion technology will make CBU more appropriate also for treating adults with such disorders. However, it has also been demonstrated that cord blood stem cells have the capacity to differentiate into other types of cells, neuronal, bone, epithelial and muscle which would have a future role to play in cell therapy and regenerative medicine. D 2005 Elsevier Inc. All rights reserved. Keywords: Cord blood; Stem cells; Tissue banking
Contents Advantages and disadvantages of using cord blood Advantages . . . . . . . . . . . . . . . . . . . Disadvantages . . . . . . . . . . . . . . . . . The current status of cord cell banking . . . . . . Current and future use of umbilical cord cells . . . Conclusion . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . .
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The first successful cord cell transplant to a sibling with Fanconi’s anaemia took place in 1988 (Gluckman et al., 1989). This proven utility of cord blood led to the establishment of cord blood banks. The first private and public banks were established in 1992. There are now some 100 cord blood banks worldwide. * Fax: +44 29 208 74097. E-mail address: [email protected].
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Historically bone marrow transplantation has been used in the treatment of patients with blood and immune disorders requiring a source of haematopoietic stem cells (HSC). Until recently, the blood remaining in the placenta and umbilical cord following the birth of a baby was discarded as a waste product. However, it has been determined that umbilical cord blood is some ten times richer than bone marrow in its proportion of progenitors of haematopoietic stem cells (Broxmeyer et al., 1990). More-
0041-008X/$ - see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.taap.2005.01.027
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over, lymphocytes in cord blood appear to be less immunologically active than those found in bone marrow (Cohen and Madrigal, 1998) and the incidence of graft versus host disease (GVHD) lower. These factors make cord blood an attractive alternative to bone marrow for a number of conditions and, following the report of the 1988 case, cord blood banks were established first in the United States and Europe and now there are many such banks worldwide both in the public and private sectors. Early transplants were to siblings but with the establishment of public cord blood banks unrelated cord cell transplants were enabled first in children and then, to a lesser extent, in adults.
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& Cord blood units do not have to be a perfect HLA match because of the reduced incidence of GVHD. This means that it is possible to use unrelated and mismatched donors (Gluckman et al., 1997; Wagner et al., 1996). While sibling donors were used in early cord blood transplants, the establishment of cord blood banks means that it has been possible increasingly to use unrelated donors. & The risk of transmission of infectious disease is diminished for cord blood because all CBU are screened for disease and any infected or contaminated units discarded. Disadvantages
Advantages and disadvantages of using cord blood Advantages & Cord blood units (CBU) are more rapidly available than bone marrow. Bone marrow is obtained from volunteer donors who are recruited by blood and transplantation services and other organisations. Donor details, including ethnicity, HLA and blood type, are held in registers. If a transplant is needed by a patient, their clinician will search the bone marrow registries for a match. The volunteer will then be approached for a bone marrow donation and tests for disease and other exclusion criteria will be carried out. This process is time consuming and it may take many weeks before a suitable donation becomes available, if at all, for the critically ill patient. There is always a risk that the volunteer will change their mind about donating. Cord blood units are stored frozen after thorough testing for contamination and specified diseases, such as hepatitis B and C and HIV, and there is no risk of last minute consent refusal. & Cord blood is less risky to collect. The collection of cord blood following delivery is a harmless process that does not affect the mother or her newborn. Cord blood can, therefore, be collected at no risk to the donor and stored, frozen, until needed. The harvesting of bone marrow is an invasive process that can cause some risk and discomfort to the donor. Bone marrow is therefore not collected until it is needed. & The number of potential donors is high. Recruitment of cord blood donors from antenatal clinics is relatively easy and only a very small number of women, from amongst those who might be willing to donate, is ever approached. Potential bone marrow donors are not so readily identifiable although many will be blood donors. & There is a decreased risk of GVHD. The cells in cord blood appear to be more Fnaive_ than their counterparts in bone marrow because of the immune immaturity of the newborn. It has also been shown been shown that the low number or absence of CD8+ natural killer (NK) T cells in cord blood may also be a relevant factor (Kim and Broxmeyer, 1996).
& The time to platelet engraftment is prolonged in the transplantation of cord blood in comparison to bone marrow (Rubinstein et al., 1998). This study also showed that engraftment time was strongly related to cell dose. & The cell dose of CBU is generally insufficient for adults. Although cord blood is enriched in haematopoietic stem cells (HSC) its volume is less than is collected from bone marrow. This makes CBU more suited to paediatric use. Clinical experience has shown that to successfully treat an adult the nucleated cell dose in the CBU must be at least 1.5 –2.0 107/kg body weight (Ballen et al., 2001; Gluckman et al., 1998), and it has been shown that a cord blood nucleated cell dose of 0.37 108/kilo increased the speed and probability of engraftment (E. Gluckman, personal communication). The Du¨sseldorf NetCord bank has had a policy of collecting only units larger than 80 ml since 1997. In these units the median number of nucleated cells was 10 T 5 108/U and only 25% of the units contained enough cells to engraft patients of 50– 70 kg. To overcome this problem multiple units of cord blood have been transplanted but usually only one CBU engrafts. Cord blood has a higher potential for in vitro proliferation than adult bone marrow (Piacibello et al., 1997), and currently a considerable body of research is being undertaken into cell expansion to overcome the cell dose problem. Most of this research is being validated in mouse models (Encabo et al., 2003; Ohishi et al., 2002) but some expanded units have already been used in the human clinical context as part of a trial (Jaroscak et al., 2003; Pecora et al., 2000). Eurocord III, funded by the EU under the Cell Factory area of FP5, will carry out an evaluation of umbilical cord blood transplant engraftment using ex vivo haematopoietic progenitors/stem cell expansion. The study will collect and compare techniques of ex vivo stem cell expansion; interact with biotechnology companies to procure cytokines and other reagents for clinical use; and compare pre-clinical animal models in mice and sheep and then design clinical protocols for ex vivo expansion of cord blood stem cells and multiple transplants. The results will be analysed and compared with the Eurocord database registry.
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& There is a risk that hereditary disorders, undiagnosed in the donor at birth, may be transmitted to the recipient.
The current status of cord cell banking Cord blood units (CBU) may be stored in for-profit private banks where parents pay for the storage of their child’s cord blood or in non-profit public banks where parents donate their child’s cord blood for unrelated use. Private banks recruit clients from obstetric clinics, via the Internet and through other promotional material. One American company, BirthCells Technology Inc., provides inducements to recruiters in the form of commission on every Fsale_ and to parents in the form of club membership for the child which gives entry to a sweepstake providing access to four $10,000 college scholarships per year. Cord blood collected for private banks may come from obstetric clinics which are far from their processing and storage facilities. Cord blood units are therefore shipped by courier/delivery service. Although some private banks do provide training materials for obstetric staff undertaking collection, they have no control over collection standards and the obstetricians or midwives collecting CBU for private banking may have little or no experience. Often the collection kits are provided directly to the parents requesting the service and they give them to their obstetrician. The risk of contamination must be higher where those responsible for the collection of cord blood do not carry out the procedure regularly and have little formal training. Although most of the larger private banks have their own processing and storage facilities others make use of Fnonprofit_ facilities. For instance, CorCell Inc., based in Philadelphia, Pennsylvania, uses the processing and storage facilities of the Elie Katz Umbilical Cord Blood Program at Bergen, New Jersey. The Elie Katz Cord Blood Program is a principally non-profit bank and providing services to CorCell Inc. allows it to offset its operating costs. Some private banks, such as the California Cryobank and Cryobanks International, were already established as tissue banks before taking CBU, the former being one of the oldest sperm banks in the United States. Two strategies are used for the collection of cord blood and are common across all types of bank. Cord blood units are collected either in utero, before placental expulsion, or ex utero, following placental expulsion. The former seems to be the preference when collection is undertaken by obstetric staff and the latter favoured by blood services staff. Research does not seem to show any advantage of the one collection method over the other (Lasky et al., 2002; Solves et al., 2003). In utero collection may give better volume at a higher risk of contamination, ex utero collection may compromise volume. Blood can be collected into syringes or into specially designed bags. The collected blood is then processed and screened for contamination and infectious diseases (HIV, hepatitis, etc.) and stored at 196 -C in liquid nitrogen.
There is a tension between private cord blood banks, which store blood for autologous or family use, and public banks, which store blood for unrelated use. There is an inference that private banks are taking out of circulation cord blood units which might otherwise be used for unrelated recipients. It is not clear that this is the case since public banks restrict their collection to a local network of hospitals and it is difficult for women outside their target population to donate. Private banks have no such restrictions. But a recent study found that women in antenatal clinics had very little knowledge about cord blood banking although the great majority of those questioned would have been willing to donate altruistically; only 14% would have elected to bank privately Fernandez et al. (2003). Private cord blood banks currently offer contracts for 18– 20 years storage. Recent research indicates that this may be reasonable as CBU stored for 15 years have been thawed successfully and been able to undergo cell expansion. Engraftment into NOD/SCID mice was comparable to fresh cord blood (Broxmeyer et al., 2003). People using private storage are usually required to pay a non-refundable enrolment fee of about $150 (175), which includes the cost of the collection kit, there will then be the costs of processing the and storing the cord blood unit, following a successful collection, which may bring the cost up to nearly $1,000 (C855). Private banks usually offer prepaid storage deals. In Europe this can range from C1,185 to C1,800 for 20 years of storage. Non-profit or public banks predominate in Europe. They too recruit from obstetric clinics but usually within a local or regional network. They will generally have a policy of collecting CBU from as wide a diversity of ethnic groups as possible and patients wishing to donate cord blood may find difficulty in doing so if they do not come from within the catchment area of a public bank. Collection methods for the CBU are effectively the same as within the private sector and will differ principally as to whether blood collection is undertaken by blood services of obstetric staff. The funding of the non-profit banks comes from a number of sources and in some cases is precarious. Sources of funding in the United States are US Federal Government support through NIH grants, contributions from charitable foundations, support from American Red Cross Biomedical Services or from running parallel private banking services. Red Cross funding also supports public banks elsewhere in the world. The only Canadian public cord cell bank has no secure long-term funding arrangements although it has received Canadian and Provincial government funding in the past and it is now actively soliciting funds from the private sector. In Europe the Jose Carreras Foundation is an important source of charitable funds and other charitable foundations, such as l’Associazone Donatrici Italiane Sangue di Cordone Ombelicale (ADISCO) in Italy, also contribute. The cord cell bank in Milan also receives Regional Government funding. State funding is also provided to
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banks in Australia, Japan, Poland and Spain. In Australia all the public banks have been funded by Commonwealth, States and Territories Governments since 2001. Previously, the banks in Queensland and New South Wales were dependent on research, charitable and community funds and grants. Public banks also receive income from charging the users of CBU and these can be substantial (in Italy sample charges are C17,000 (Bologna) and C17,675 (Milan)). But use is low with only 1 – 3% of units stored being used in any one year while the setting up an maintenance costs are high. Moreover, public banks which supply data to international registries have to undertake sophisticated tissue typing and DNA tests which private banks storing for autologous use do not. Both types of bank would be expected to carry out contamination and communicable disease tests. Private banks pass these processing costs on to their customers. However, tissue typing costs are high and these tests would not routinely be offered by private banks in their storage contracts. Bone Marrow Donors Worldwide, based in Leiden in the Netherlands, is the largest clearing house for cord blood units in public cord cell banks, and in May 2004 it had registered over 167,000 CBU being held in over 18 countries. The number of CBU held in private cord blood banks is unknown but the Cord Blood Registry alone claims to hold nearly 60,000 and Cryo-Cell International over 60,000. The Royal Australia and New Zealand College of Obstetricians and Gynaecologists (RANZCOG) in its 2003 statement on umbilical cord blood banking (RANZCOG, 2003) estimated that 200,000 CBU are held in private banks for autologous use. This has probably considerably increased by now. Outside the United States, there appears to be little knowledge among the public about umbilical cord blood banking. A survey in Canada (Fernandez et al., 2003) has shown that a high proportion (70%) of women attending antenatal classes at a regional hospital had a poor or very poor knowledge of cord blood banking. This is surprising since one might expect them to be actively targeted by private banks in the United States and Canada. Of the 443 respondents to a questionnaire 86% were willing to make altruistic donations of cord blood with only 14% preferring to elect private banking. Research was considered an acceptable use of cord blood by the majority of respondents. It would therefore seem that umbilical cord blood is a largely untapped resource, the logical consequence of which would be to routinely store CBU with women being able to elect private storage if they wished. However, it is likely that the costs of public cord blood banking would mitigate against this. At present, quality standards for the storage of cord blood are mostly ensured through a number of voluntary accreditation schemes and there is little statutory regulation. Recently, the European Directive (2004/23/EC of 31 March 2004) on setting standards for quality and
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safety for the donation, procurement, testing, processing, preservation, storage and distribution of human tissues and cells came into force. This tissue banking directive will apply to all biobanks, including cord cell banks (though not banks storing blood or blood products), in the public sector. Other countries, notably Australia and Germany, impose GMP standards. However, elsewhere standards apply which have been developed by bone marrow transplant organisations or blood services such as the Foundation for the Accreditation of Cellular Therapy and the American Association of Blood Banks. Standards for registries holding details of haematopoietic stem cell donors are set by the World Marrow Donor Association. In the United States the FDA is in the process of drawing up tissue banking regulations and it has been agreed that the Health Resources and Services Administration will put $10,000,000 into funding a National Cord Blood Stem Cell Bank Program but this expenditure will await a report on the issue from the Institute of Medicine. In the meantime there is disagreement between among cord blood banks and registries as to how the program should work (Reed, 2004). In Europe the current mood is principally against private cord cell banking. A recent opinion on the ethical aspects of umbilical cord blood banking (European Group on Ethics, 2004) states that the likelihood of an individual to need an autologous graft of HSC was, at the present time, non-existent and that so far there is no proven utility of other stem cells from cord blood. These would have to meet stringent criteria before they could be used clinically and there was no evidence, if they did, that the subject’s own bone marrow or a well-matched donation from an allogeneic donor would not suffice. The Opinion mentions the draft recommendation of the European Health Committee of the Council of Europe which states, ‘‘the promotion of donation for autologous use should not be supported by member States or their health services.’’ In February 2002 the French National Consultative Ethics Committee, in its Opinion No. 74, warns of private banks that ‘‘. . . setting up such banks is likely to contradict the principle of solidarity, without which no society can survive’’ and that ‘‘Such banks raise hopes of utopia and disguise a mercantile project using assistance to children as a screen.’’ Private cord blood banking is prohibited by law in Italy. In the United States, on the other hand, private cord blood banks have had relatively free rein. However, they are now coming under attack from within the mercantile system itself. The patenting of the processing and storage procedures for cord blood banking in the United States and Europe has threatened cord blood banks with the additional cost of having to operate under license. In April 2003, after a four year legal battle, the European patent was revoked. More recently, the patent holder has successfully pursued a lawsuit for patent infringement against four private cord blood banks in the United States being awarded $7.1
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Table 1 Diseases treated by cord blood transplantation Malignant diseases Acute lymphocytic leukaemia Acute myelocytic leukaemia Chronic myelogeneous leukaemia Juvenile chronic myelogeneous leukaemia Myelodysplastic syndrome Neuroblastoma Non-malignant diseases Adrenoleukodystrophy Amegakaryocytic thrombocytopenia Blackfan – Diamond syndrome Dyskeratosis congenital Fanconi’s anaemia Globoid cell leukodystrophy Gunther disease Hunter syndrome Hurler syndrome Idiopathic aplastic anaemia Kostmann syndrome Lesch – Nyhan syndrome Osteopetrosis Severe combined immune deficiency Thalassaemia X-linked lymphoproliferative syndrome Adapted from Ballen et al., 2001.
million in damages. This judgement is being challenged. Pharmastem is now pursuing another five private cord blood banks.
Current and future use of umbilical cord cells To recapitulate, umbilical cord blood is some ten times richer in haematopoietic stem cells than bone marrow but the volume collected is smaller. Success and speed of engraftment is related to the number of stem cells transplanted. Cord blood has, as a result, been more suitable for paediatric than adult use but advances in cell expansion technology mean that cord blood units may become more suitable for adult use in the future. Until then, cord cell transplants may continue to be regarded as experimental by many physicians. However, in the longer term, the demand for CBU may increase for other reasons. Umbilical cord blood is being used in the treatment of an increasing number of malignant and non-malignant diseases. Table 1 shows the diseases treated by cord blood transplantation so far in some 3500 transplants worldwide. But the focus here is still on haematopoietic stem cells. Recently it has been discovered that cord blood also contains pluripotent stem cells which have the capacity to develop into neuronal, muscle and bone forming cells (Ko¨gler et al., 2004) and into endothelial cells (Bompais et al., 2004; Le Ricousse-Roussanne et al., 2004). It has also been reported that autologous bone marrow cell trans-
plantation has been used successfully in the treatment of patients with severe heart failure (Perin et al., 2003). It is likely that cord blood cells would have similar properties, and in the longer term future, it would seem that stem cells from umbilical cord blood might have a significant role to play in cell therapy and regenerative medicine. It is therefore not surprising to find biotech companies being established alongside cord blood banking facilities. In Europe, Kourion Therapeutics AG was established alongside the non-profit Du¨sseldorf Cord Blood Bank with the director of the Cord Blood Bank as a scientific advisor and on the board of directors of the company. The company, which estimates that the total cell therapy market will amount to more than $30 billion by the end of the decade, is developing cell therapies for the treatment of bone defects and for myocardial regeneration using a proprietary lineage of unrestricted somatic stem cells (USSC) isolated from umbilical cord blood. Kourion Therapeutics has recently been taken over by the American company Viacell, the parent company of the Viacord private cord blood bank. Also in the for profit cord blood banking sector, Cryo-Cell Europe has recently acquired MainGen GmbH, a company located in Frankfurt that specialises in the processing, preparation and expansion of stem cells from cord blood and bone marrow with interests in cell and gene therapy.
Conclusion With the perfection of cell expansion technology, stem cells from umbilical cord blood may well become a preferred option for the treatment of those diseases where bone marrow is currently used. This will also be dependent on reliable, high-quality banking standards worldwide. It is clear that cell therapy could also become a major use for cord blood stem cells in the not too distant future. These cells have the advantage that they are more plentiful and more accessible than adult stem cells and they have already been shown to differentiate into a number of different cell types other than haematopoietic cells. They would be ethically more acceptable than embryonic stem cells. But there are a number of questions that need to be answered. Where should these stem cells be stored? The storage costs of the private sector might look like good value if the potential use of cord cells includes cell therapy and regenerative medicine. But this will limit access to those using private storage. Certainly the routine collection of cord blood from all newborn would overcome the problems of supply and diversity. If this could be publicly funded this would ensure access by all individuals to compatible cells, if not their own. But cost will be a major inhibitor, particularly as current attitudes are skewed towards use only for blood disorders and long-term strategies for the storage of cells for other purposes seem unlikely. Should there be competition between the public and private sectors for such a resource?
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Who should bear the costs? JJ Nietfeld (personal communication) in a recent report to the Netherlands Organisation for Health Research and Development (ZonMw) has suggested that, if cell expansion becomes standardised, where stem cells are stored for personal use part of the cells could be donated for use by third parties (Chapter 5, Section 2.3). He also suggests that banks might obtain extra revenue from the sale of a very small portion (2%) of the stem cells for research. The private sector is already investing in the development of unrestricted somatic stem cells from cord blood for use in cellular therapies and will wish to more than recoup its costs in what it sees as a $30 billion market. In Europe the biggest purchasers will be the national health services treating patients but in countries like the UK such costly therapies may be less widely available in the public sector. The issue of access to these new therapies is a question that needs to be addressed.
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