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Advantages & Limitations to cord blood banking
Video: What is cord blood banking
Advantages
The use of cord blood stem cells as a suitable graft for transplantation has several clear advantages over bone marrow and peripheral stem cells obtained from a donor.
A clear advantage over other sources of haematopoietic stem cells is the fact that cord blood cryopreserved in private or public banks could be located and released almost immediately, since it is already tested and banked. Locating a donor for bone marrow or peripheral blood may takes several weeks or even months which in some cases this delay could have a serious effect on the progression of the disease. Furthermore, suitable adult donors identified through a computerized registry may be difficult to locate because of:
- A change in their geographic location
- Donors may decline to participate
- Donors may be rejected due to pregnancy, illness or social behaviour.
In addition, the acquisition of bone marrow from an adult donor requires hospitalization and anaesthesia and may be accompanied by postoperative pain (the bone marrow is usually aspirated from the pelvic crest under epidural anaesthesia). Peripheral blood stem cell units are collected by outpatient aphaeresis procedures (no need for hospitalization). Donors receive 4–5 injections of a mobilizing agent prior to the collection in order to stimulate the bone marrow to release more stem cells in the circulating blood to enable the stem cell collection (aphaeresis). In contrast, cord blood collection is a simple and safe procedure without interfering either with the mother or the infant.
Probably the most significant advantage of umbilical cord blood as a source of hematopoietic progenitor cell graft is that a greater HLA mismatch is tolerated by the recipient than in the case with bone marrow transplant. In other words, cord blood may be used in transplants without requiring 100% compatibility between patient (recipient) and donor. This is attributed to the fact that the haematopoietic stem cells of cord blood are less mature than bone marrow stem cells (more naive cells) and are less recognized by the patients’ immune system as a foreign body. As a consequence, the frequency of GvHD in cord blood transplants is lower and appears to be less severe compared to bone marrow transplants. There have been around 20000 unrelated-donor transplants performed in more than 50 locations around the world and most of these transplants, were HLA mismatched between donor and recipient at 1 or 2 HLA antigens. Efficacy (success) has been demonstrated in both children and adults with different types of leukemia and children with haemoglobinopathies, immunodeficiency syndromes, bone marrow failure syndromes and inborn errors of metabolism.
Limitations
The greatest limitation to the use of cord blood appears to be the total cell dose in a cryopreserved unit (measured as either the total number of nucleated cells or the CD34+ stem cell count) and as a consequence, cord blood units may not be suitable to patients of larger body mass and can only be used as a graft in a single transplant procedure.
Furthermore, due to the cell dose limitation, cord blood transplants have been shown to take longer time for engraftment as opposed to bone marrow. Mean engraftment time is approximately 30 days whereas in bone marrow transplants the mean engraftment time is 20 days. The extended engraftment time exposes the patient to infections for a longer period and increases the risk of failure of the transplant procedure.
Units that have been divided in aliquots (unnecessarily separated portions) in either vials or cryobags, do not have sufficient stem cells to support a transplant as a portion and therefore will have to be reconstituted into a single unit for application to a patient.
The table below summarizes the advantages and limitations of Cord Blood Stem Cell Use compared to other sources
|
Advantages |
Limitations |
|
Readily available |
Low cell dosage |
|
Easy and painless procedure |
Slower engraftment |
|
Full compatibility not essential |
|
|
Less GvHD |
|
Strategies to overcome limitations
As the need in using umbilical cord blood in adults has grown, experimental procedures and strategies are being developed and applied in clinical trials in order to overcome the cell dose limitation and slow engraftment.
- Ex vivo expansion of stem cells
- Multiple umbilical cord blood unit use in the same recipient
- Reduced Intensity/Non-myeloablative stem cell transplantation
- Intra–Bone Marrow Injection
The aim of ex vivo expansion is to create culture systems whereby under certain conditions the nucleated cells as well as the stem cells will be stimulated to multiply themselves several times with the final aim of creating a rich cord blood unit that will have sufficient cells to support the transplant. Lifeline cryopreserves umbilical cord blood units in double compartment cryobags. In the event where the cell dose is not sufficient to support the therapy of, for example an adult patient, one of the compartments can be detached, multiplied in the laboratory and administered with the remaining portion (compartment) to the patient.
Ex vivo expansion protocols are being studied at several centres around the world. One such study is being conducted at the world renowned M.D. Anderson Cancer centre in collaboration with a biotechnology company known as Gamida Cell in a joint venture with TEVA Pharmaceuticals. Gamida Cells flagship product, StemEx®, is currently being studied as a treatment for haematological malignancies or blood cancers including leukemia and lymphoma. Already the results of Phase I/II studies have been successful, hence approval has been granted to expand research in an open, global, pivotal Phase II/III study called ExCell, recruiting patients at prestigious cord blood transplant centres in the US, Europe and Israel. The results of the Phase i/ii trial have been published as follows:
Lima M. et al, Transplantation of ex vivo expanded cord blood cells using the copper chelator tetraethylenepentamine: a phase I/II clinical trial, Bone Marrow Transplantation (2008), 1–8
Another such study is being conducted at the Fred Hutchinson Cancer Research Center where researchers have found a way to make umbilical cord blood transplants safer and more effective. The technology, developed in the lab and being tested in a phase I clinical trial of leukemia patients, expands the number of stem cells in a unit of cord blood to give patients a safer, more rapid engraftment and recovery after a transplant. By manipulating the notch pathway, Delaney and colleagues were able to optimize and expand the number of stem cells in the cord blood in the lab. They then infused high-risk leukemia patients with the cells in a phase I clinical trial. The results were very promising. For the 10 patients reported in the study, it took an average of 14 days for the stem cells to engraft and make enough new white blood cells, compared to an average of about 4 weeks using cells that had not been expanded. The age range of the patients was from 3 to 43. While early results are encouraging, the researchers say the technique needs to be replicated in randomized trials and tested in other centres. Researchers are still enrolling patients in the trial (2009), which they hope to move to phase II and involve other research centres.
Reference
Delaney C et al. (2010) Notch-mediated expansion of human cord blood progenitor cells capable of rapid myeloid reconstitution, Nature Medicine 16, 232–236
Multiple umbilical cord blood unit use in the same recipient
In an effort to increase the cell dose to adult patients in need of haematopoietic stem cell transplants, transplant specialists are now routinely using multiple cord blood units in a single application for adult patients who are in need of a higher number of stem cells (stem cell dose). Double UCBT is a feasible, safe and effective transplantation strategy for patients that have life-threatening haematological disorders who need a haematopoietic stem cell transplant but lack a HLA-matched related or unrelated donor. It is an attractive option, especially for adults who are typically not eligible for single UCBT because of limitations of cell dose. Besides being rapidly available, an acceptable double unit graft can be identified for the majority of patients. The rates of engraftment, transplant-related mortality, GVHD and survival are similar to those seen with single UCBT and unrelated donor bone marrow. Ongoing studies are investigating the more general applicability of double UCBT in a multi-institutional setting.
Reference:
Majhail NS Brunstein CG and Wagner JE (2006) Double umbilical cord blood transplantation Current Opinion in Immunology 18:571–575
Reduced Intensity or Non myeloablative approach
Reduced intensity conditioning refers to a conditioning regimen that uses less chemotherapy and radiation than the standard regimen which totally destroys the bone marrow cells (myeloablation). The goal of using a reduced intensity regimen is to decrease the transplant-related complications, toxicity and mortality and allow for the reconstitution of the bone marrow using fewer stem cells.
Cutler C and Ballen K (2009) Reduced-intensity conditioning and umbilical cord blood transplantation in adults Bone Marrow Transplantation 44, 667–671
Intra bone marrow injection of cord blood haematopoietic stem cells is a novel approach whereby instead of system administration of such cells in a transplant, the cells are injected directly into the bone marrow which is the site for haematopoiesis. This approach has reached phase I/Phase II clinical trials with very promising results.
Studies have shown that direct intrabone transplantation of cord-blood cells could improve haematological recovery as a result of better engraftment /stem-cell homing. This postulation was made on the basis of the following findings: stem cells recirculate in animals irradiated with limb shielding; only a small proportion (10–15%) of cells injected intravenously migrate to haematopoietic sites, possibly because most cells are lost in other organs; in a mouse model, direct intrabone injection of haemopoietic cells resulted in repopulation of the marrow of lethally irradiated mice that was ten-times more efficient than when haematopoietic cells were injected intravenously.
Furthermore direct intrabone cord-blood transplantation is associated with a high rate of successful donor engraftment, even when low numbers of HLA mismatched cord-blood cells are transplanted. Thus, this technique potentially can be applied to significant numbers of adult patients. The decreased incidence of acute graft-versus-host disease is intriguing. If these findings are proven in a larger series of patients, direct intrabone injection will have the potential to affect the current practice of haematopoietic stem-cell transplantation.
References
Frassoni F. et al,(2008) Direct intrabone transplant of unrelated cord-blood cells in acute leukaemia: a phase I/II study. Lancet Oncology ; 9: 831–39
Frassoni F. (2010) Intra-bone route of administration offers new perspectives for safer transplantation of hematopoietic stem cells Cytotherapy; 12: 5–6
