THE IMPORTANCE OF UMBILICAL CORD BLOOD BANKING

for present and future cell therapies

There are many reasons that umbilical cord blood (UCB) has become a major alternative donor source for blood and marrow transplantation.

UCB can be collected from the umbilical cord and placenta after birth. The blood volume of about 80 to 100 ml contains approximately one billion blood cells consisting of one to ten million CD34+ stem and progenitor cells that can be used as donor cells for bone marrow transplantations. Moreover, stem cells found in UCB have the same properties as those isolated from the bone marrow but offer advantages that bone marrow cells do not. One main advantage is UCB is easily collected with little risk to the mother or baby. A second advantage is that the patient better tolerates a mismatched UCB unit as opposed to a mismatched bone marrow donor unit. Matching of the donor and the recipient is important for allogeneic transplants. Usually, a perfect match at eight or 10 HLA antigens is sought in order to reduce graft rejection and graft versus host disease. Finding a perfect match reduces the availability of a donor unit to those that have identical HLA antigens. Interestingly, the analysis of transplant data has revealed that a single-mismatched UCB unit (mismatched at one HLA antigen between the patient and donor) results in equal survival as a fully matched bone marrow unit. This translates into a larger available donor pool with UCB versus bone marrow because a perfect match is not required (NEJM 2007).

The fi rst single unit UCB transplant was conducted in 1988 using a sibling UCB unit. This fi rst transplant, which took place in France, was successful and the patient from that procedure is still alive today. During the early years of UCB transplants, the therapy was limited to pediatric patients because the low number of cells in a typical UCB indicated that adult transplants would be risky. Currently, there have been over 30,000 transplants using UCB in children and adults.

Improvements in matching and adult patient selection have also led to more successful adult transplants. Studies have since demonstrated that increased cell dose yields better outcomes. For many adult transplants, two UCB units are used and they can each be partially mismatched to each other and the patient and still yield positive outcomes. As transplant centres become more familiar with using UCB as a donor source and as innovations lead to an increase in adult UCB transplants, the demand for donors will increase.1

Public and Family Banks:

Currently, public banks that are usually funded by local or federal levels of government are the ones to collect UCB. Public access banks will collect only at designated hospitals and keep a wide range of different HLA-types

Bottom Left: A UCB collection bag. Bottom Right: Human UCB in a blood vessel in a mouse liver post transplantation. The blue are nuclei and the blue with the yellow-green dots around it is a human blood cell with the mitochondria labeled so it can be distinguished from the mouse cells.

on hand. There is no fee for the collection or storage and the UCB unit’s HLA type is uploaded into an international registry so patients around the world have access to suitable units.

When a unit is released to a transplant centre, the public bank levies a charge of $30,000 to $50,000. In Canada, for example, this fee is paid by provincial government medical plans, such as OHIP in Ontario. In the U.S., many health insurance companies cover these fees. One of the longest running public UCB banks is the National Cord Blood Program run by the New York Blood Center that collects at eight affi liated hospitals in the New York area, Virginia and Ohio.2,3

An alternative to the public bank system is private banks (also known as family banks), which are companies that charge a fee for the collection and storage of the UCB unit, which is then held for the family. Family banks such as Insception-Lifebanks in Canada4 and Cord Blood Registry in the U.S. were established in the mid 1990s.

Until very recently there were only two public banks in Canada, one in Alberta that was funded by a provincial grant, and the second located in Québec, run by HemaQuébec. The Canadian national umbilical cord blood bank started collecting units on September 30, 2013.5 In doing so it became the last of the G8 countries to start a national program for collecting and storing umbilical cord blood units for the general public.

In Canada and the U.S., only about three to fi ve per cent of all births will result in cord blood storage, either in private or public banks. Considering there are over three million births annually in these two countries, millions of units are currently being tossed away as biological waste. For non-caucasians, the chance of fi nding a match can be very low, so there is a need increase UCB banking, especially for ethnic Canadians.

The establishment of a public bank will facilitate the storage of samples for use by Canadians, but it should also provide units for international patients, through international registries such as Euro Cord and Net Cord. The New York Blood Center has donated stored units to over 25 countries, including six transplant centres in Canada. With the establishment of a Canadian public bank, we will now not only be able to provide potential units for Canadian patients, but Canada will now be able to contribute to the world-wide pool of available units instead of just being an end user of UCB.

What are UCB stem cells used for?

In the last fi ve years there has been an increase in UCB use for bone marrow transplants in pediatric patients and more recently, in adults. The 2011 transplant data from the New York Blood Center shows that 62 per cent of the UCB units were used to treat leukemia and another 26 per cent were used to treat other blood-based diseases. Interestingly, six per cent were used to treat metabolic diseases such as Hurler’s disease or Tay Sachs disease. Although half of these units were used to treat pediatric patients, roughly 30 per cent were used on adults.3

The data from private banks shows a different profi le of the diseases treated and highlights an interesting difference between public and private banks. For example, Insception-LifeBanks (a large Canadian bank) has released units that were used to treat blood-related diseases similar to those treated with units from public banks. In these cases as would be expected a sibling was usually the donor. But units were also released that were used by the donors themselves. In other words, the unit was used autologously. In these cases the patient’s own UCB unit is considered disease free because the treatment is for a non-blood-based disorder.

Autologous UCB transplantation was part of the treatment regimen for retinoblastoma (eye cancer), Type 1 diabetes and Cerebral Palsy.6,7,8 In the retinoblastoma cases, aggressive treatments to eradicate the cancer can damage the immune system, so having a source of blood stem cells available allowed doctors to treat the eye cancer and correct any subsequent damage to the immune system by using the patient’s own UCB cells. Likewise, using UCB for the treatment of Type 1 diabetes and Cerebral Palsy is based on properties of UCB that enhance wound healing and can modulate the immune system. Mature cells in the UCB unit, not the stem cells, are known to secrete a variety of proteins called cytokines that are involved in controlling the body’s response to injury from external forces, such as oxygen depletion during birth leading to Cerebral Palsy, or from internal factors such as an autoimmune reaction that damages islet cells, resulting in Type 1 diabetes. Treatments for these diseases are still experimental and in the clinical trial phase, but indicate there may be a wider use for UCB in the future.

Dr. Kurtzberg at Duke University has been conducting trials using a patient’s own UCB to treat Cerebral Palsy since 2010. The concept is that the neural damage causing Cerebral

Palsy can be reduced by the infusion of the patient’s own UCB blood, which then helps reduce inflammation of the brain tissue and increases blood flow to the damaged area, thus reducing the amount of neural damage. In the case of Type 1 diabetes, the hypothesis is that UCB will reduce the autoimmune initiated damage of the islets, thus slowing down the progression of the disease. In both Cerebral Palsy and Type 1 diabetes the UCB treatment does not eradicate the disease but is expected to slow down its progression.

What these diverse treatments bring to light is that there are allogeneic (non-self) uses of UCB, which is the main use of the UCB units from public banks. It is logical that the treatment of blood cancers does not use the patient’s own UCB unit as it may contain cells that are cancerous. Therefore, a healthy UCB unit offers the best treatment. But in the case of a non-blood disorder, the patient’s own UCB unit would be healthy and present less risk for transplantation, which is why autologous UCB, stored in private banks, has been used for the Cerebral Palsy treatment study.

The ability of UCB cells to enhance tissue healing has also been demonstrated in pre-clinical animal studies. For example, UCB has been shown to reduce late stage tissue damage in a model of spinal cord injury.9 Therefore, it is possible that in the future, UCB can be used to treat non-healing diabetic wounds, tissue ischemia, traumatic brain injury and spinal cord injury.

The future of UCB as a source of cells for cell based therapies:

UCB is becoming a standard of care for the treatment of blood disorders and cancers. At some centres, it is already preferred over bone marrow stem cells as a donor source. The problem with collecting and storing such cells for transplant is the cost of doing so. The Canadian National Cord Blood Program run by the Canadian Blood Services was started with $35.5 million from the federal, provincial and territorial governments. Canadian Blood Services is tasked with raising another $12.5 million to ensure the costs of running the bank is covered.5 There are successful examples of public banks in many other countries and in the U.S. there are multiple public banks but even with the fees collected from units sent for transplant, it is a costly endeavor that requires, and merits, the support of all levels of government and the public.

Public banks in Canada will collect from a few locations, including Ottawa and Mississauga, ON, as well as in Edmonton, AB. Their goal is to amass a sufficiently diverse collection of units to cover everyone in Canada. It has been estimated that a diverse collection of 20,000 units, the budgeted goal of the Canadian Bank, should be sufficient. In theory this is the expectation, but even with over 10 million registered bone marrow donors, many people requiring a bone marrow transplant cannot find a suitable donor. With only three to five per cent of all UCB samples being collected and stored, the importance of increasing collections cannot be undermined. Public and private banks currently store over two million units worldwide, but this inventory needs to be increased.10

An interesting concept that may address the funding problems public banks face is a hybrid bank that has both a public and private arm. The private arm would help to generate the revenue that a public bank can’t generate on its own. One such bank, CORD:USE Cord Blood Bank was founded and run by four of the world’s leading transplant physicians and experts, who are all avid public bank supporters. The CORD:USE private arm is aptly referred to as the family bank, since a unit stored by the paying family will be saved for use by the family, and its public bank arm will store units from the donor that will be accessible by all.

The Canadian naTional Cord Blood Program run By The Canadian Blood ServiCeS waS STarTed wiTh $35.5 million from The federal, ProvinCial and TerriTorial governmenTS. Canadian Blood ServiCeS iS TaSked wiTh raiSing anoTher $12.5 million To enSure The CoSTS of running The Bank iS Covered.

References:

1. Ballen, Blood, 2013 122: 491-498 2. National Marrow Donor Program: http:// bethematch.org 3. New York Blood Center: http://www. nationalcordbloodprogram.org/ 4. Insception-Life Bank: www.insception. com 5. One Match, Canadian National UCB program: www.blood.ca 6. www.clinicaltrials.gov 7. Cerebral Palsy: Bone Marrow Transplant. 2013 Jul;48(7):890-900. 8. Type 1 Diabetes: Pediatr Diabetes. 2013

Sep 19. doi: 10.1111/pedi.12072. [Epub ahead of print]. 9. Spinal Cord Injury: Spine (Phila Pa 1976). 2010 Jul 15;35(16):1520-6. 10. Parent’s Guide to Cord Blood Banking: http://parentsguidecordblood.org/

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