The current situation
Over the last three decades, there have been over 55,000 umbilical cord blood (UCB) transplants worldwide used to treat more than 80 life-threatening and/or debilitating diseases. Furthermore, UCB is now being used in regenerative medicine and is in clinical trials to treat neurological conditions, cerebral palsy, autism, diabetes and cardiac disease to name a few.
Autologous and allogeneic UCB transplantation
Cord blood transplants may be autologous where the UCB has been collected from the individual’s own umbilical cord at the time of birth. Alternatively, allogeneic cord blood transplantation utilises UCB from a matched donor who may be a sibling or an unrelated individual.
Increasingly, parents are choosing to bank their children’s UCB in private family banks. Privately banked UCB has several well accepted therapeutic applications with most cases using UCB from a sibling. These sibling transplants have mainly been to treat haematological (blood and bone marrow) disorders such as leukaemia, sickle cell disease and thalassaemia, however sibling transplantation in the setting of regenerative medicine is increasing.
For autologous, (self to self) transplantation UCB is used infrequently for haematological diseases and it’s use is more prevalent in regenerative medicine. Some of the reasons for this balance of use are outlined below and the potential for change is addressed.
Why can autologous UCB not be used for certain diseases?
Non-malignant haematological (blood and bone marrow) diseases:
People with genetically based disorders such as sickle cell disease or thalassaemia, cannot use their own UCB and need stem cells from a closely matched healthy donor. This is because the success of treatment depends on the healthy donor stem cells with no mutations, regenerating normal bone marrow function in the patient following high doses of chemotherapy which is designed to destroy genetically abnormal cells which are causing disease.
Malignant haematological diseases:
In the case of allogeneic transplantation for leukaemias and other blood and bone marrow cancers, the aim of donor stem cell therapy is two-fold:
- a) As part of a transplant protocol, chemotherapy is given to patients to destroy the cancer cells, but this has the unfortunate complication of damaging bone marrow function as a side effect. The healthy donor stem cells that are transplanted can regenerate the bone marrow system in the patient following chemotherapy.
- b) There is an added benefit in that the donor cells are capable of recognising and killing remaining tumour cells in the patient after administration of the chemotherapy as part of the treatment protocol. This is called the “Graft vs Malignancy” effect.
The recognition of cancer cells in the patient is only possible if the transplanted cells are from a different person, as subtle differences in their genetic makeup (even though they are a close match) will enable them to detect the patient’s cancer cells as “non-self” and attack them via the Graft vs Malignancy effect.
A question that is often asked is whether an individual can be treated for a blood or bone marrow cancer using their own autologous cord blood. The answer is “probably not” due to the fact that genetic changes linked to some leukaemias and other haematological cancers arise during foetal development in the uterus, so these flaws will be present in the UCB of the baby at birth. Under these circumstances, a transplant using cells from a person’s own UCB would have little if any beneficial Graft vs Malignancy effect. See further comment below*.
What can autologous UCB be used for?
*The importance of determining whether UCB carries genetic mutations:
As mentioned above, some people will have stem cells with genetic changes present in their UCB at birth that pre-dispose them to certain haematological cancers. However, it is important to note that only some blood and bone marrow cancers arise from genetic mutations that are present in foetal development. Where the genetic flaw(s) are present during development of the child in “in utero” these are referred to as “constitutive” changes. These are most commonly noted in childhood leukaemias.
Alternatively, it is recognised that not all haematological malignancies are constitutive, and in such cases, the genetic defects can be “acquired” due to various causative factors that are encountered during life such as viruses and environmental influences. This important point means that it should not be assumed that autologous UCB transplantation is automatically contra-indicated.
With sophisticated molecular testing, small sub samples of UCB can potentially be screened for the presence of certain known genetic mutations and if all clear, mutations that are present may have been acquired and thus the UCB could potentially be used in an autologous transplant. Although such a transplant would not offer a Graft vs Malignancy effect as this requires donor cells, the autologous UCB cells would be capable of restoring and rescuing the function of the bone marrow system after chemotherapy.
Autologous UCB transplantation and bone marrow rescue
Helping with unexpected failed engraftment problems:
In the case of allogeneic transplants, sometimes unexpectedly, the donor stem cells do not engraft satisfactorily in the patient. This is called graft failure and is an extremely serious complication which means that the donor stem cells do not “take” or “settle and grow” in the patient’s bone marrow. Graft failure causes the patient to be very vulnerable to infection, bleeding and anaemia and results in hospitalisation and reliance on antibiotics and blood transfusions. In such cases, more stem cells are required as a “back-up” to “rescue” the bone marrow function.
The process of using bone marrow or peripheral blood stem cells as a rescue strategy is a recognised procedure used for cases of graft failure in donor or autologous transplants. If the individual already has their own UCB stem cells banked, then these could potentially be used to help repopulate the bone marrow that has been damaged by chemotherapy. Clearly there would be no Graft vs Malignancy effect with autologous use but when faced with the medical emergency of graft failure, the primary aim is to restore bone marrow function. Although not being widely utilised in this manner at present, pre-banked UCB may become accepted as a useful resource in such circumstances.
Planned rescue of bone marrow function:
There are some solid tumour, non-haematological cancers where autologous UCB stem cell transplantation is used as part of a planned approach. One such example involves the treatment of children or young adults with certain types of brain tumour such as neuroblastoma and medulloblastoma.
In certain treatment protocols, patients receive very high doses of chemotherapy aiming to destroy their tumour but before that, some of their own healthy haematopoietic stem cells from their bone marrow or peripheral blood (following use of drugs to coax stem cells from their bone marrow into their blood) are collected and stored in the frozen state ready for use when the inevitable bone marrow damage occurs. The patient’s own cells which have been proactively collected and frozen are thawed are re-infused to rescue the bone marrow function following chemotherapy. In such cases, the disease being treated would not be present in the individual’s UCB. For that reason, stem cells in their pre-banked UCB would potentially be extremely valuable to supplement a transplant for bone marrow rescue purposes.
Regenerative medicine and autologous UCB
Regenerative medicine utilises cellular therapeutics in conjunction with various technologies and other treatments to repair or restore damaged tissues and organs. Regenerative medicine has typically NOT been associated with the treatment of cancers although there are now some exceptions.
The examples of autologous use in cerebral palsy and diabetes are highlighted below.
Mesenchymal stem cells – the key players
Mesenchymal stem cells (MSCs) which are found in several sources including but not limited to bone marrow, adipose tissue, UCB, and cord tissue are pivotal in regenerative medicine. MSCs can differentiate into different cell types but more importantly, they have the ability to damp down overactive immune responses, they have potent anti-inflammatory properties and can promote healing at the site of tissue damage.
Both autologous and allogeneic UCB products are being used in clinical trials as valuable sources of these potent MSCs to treat various conditions. The examples of autologous use in cerebral palsy and diabetes are highlighted below:
Cerebral palsy
There has been considerable interest in the use of pre-banked UCB in autologous transplantation for the treatment of children with hypoxic brain damage, typically incurred at the time of birth resulting in cerebral palsy. Clinical trials have shown the treatments to be safe and encouraging results have been noted in children in terms of improved cognitive and motor function. Much of this work has been undertaken at the Duke University Hospital in the USA and Smart cells has released 13 UCB samples to Duke on behalf of children with cerebral palsy and related conditions.
Diabetes
In Australia, a team have undertaken a world-first clinical investigation known as the CoRD study, to assess whether cells found UCB can stop the immune destruction of critical stem cells in the pancreas and protect children at risk from developing diabetes. The study has been treating high-risk children (who have a close relative with type 1 diabetes) and have their UCB stored in a cord blood bank. The pilot study involves the children receiving an infusion of their own pre-banked cord blood. The team hope that the study will help in the understanding of the immune system in children at risk of developing diabetes and may highlight ways to prevent this lifelong disease.
Future directions for autologous UCB based therapies
We cannot guess what the future holds for cellular therapies but there is no doubt that this is a rapidly growing area and will feature increasingly in 21st century medicine. Many novel therapies are being developed and two particularly relevant recent game changing strategies now helping many patients are highlighted below.
Cell expansion:
In the current clinical era, remarkable research in the field has helped develop cell expansion technologies to overcome the limitations of UCB cell numbers which can be low at the time of collection. There are several specialist transplant centres worldwide using laboratory expanded UCB to successfully treat adult patients for whom standard UCB cell numbers may not have been sufficient. This therapeutic approach which has gained FDA approval, is becoming well accepted in haematopoietic stem cell transplantation and is being utilised in specialist centres globally.
Tailored immunotherapy:
The use of customised techniques to harness the potential of specific stem cell types for targeted immunotherapy in the field of blood and bone marrow cancers is an exciting development.
Currently in these therapeutic strategies, a portion of a patient’s own immune cells are genetically modified in a laboratory and then re-infused back to the patient to recognise, target and help to destroy their cancer. However, the science is evolving and new work is showing that UCB can be utilised in this way and the results are looking favourable.
Conclusions
Private UCB banking has increased in popularity over the last 15-20 years. As those individuals who have their UCB banked grow older, they may develop conditions where their UCB stem cells become a very relevant and readily available resource for their own use in a particular treatment. This could be for blood/bone marrow conditions to counteract graft failure in a donor transplant or to augment stem cells from another source, for regenerative medicine purposes or to be used as the starting material for targeted immunotherapy.
There is a genuine potential for these treatment strategies to utilise UCB as a valuable source of stem cells and although mostly involving the public banking domain initially, while experience and data is gathered, ultimately these initiatives may be extended to privately banked UCB collections.
References
https://www.nature.com/articles/pr2017236
https://onlinelibrary.wiley.com/doi/10.1111/jpc.15329
https://clinicaltrials.gov/study/NCT04243408
https://parentsguidecordblood.org/en/news/meta-analysis-cord-blood-cerebral-palsy
https://parentsguidecordblood.org/en/news/asias-cord-blood-story
https://clinicaltrials.gov/study/NCT03019640
