- COMING SOON: Meet the register developer: how is Sarah Rogers ensuring the diversity of Anthony Nolan’s register and what does this mean for patients?
- Meet the cord collector: what is a day in the life of Chris Fay?
- Meet the scientist: how does Daniel Gibson ensure the collected cord blood produces a high quality therapeutic product?
How did you get involved in working with AN?
I was training as a PE teacher when my son, Noah, who was 4 at that time, was diagnosed with a chronic granulomatous disease, a blood disorder. He underwent a bone marrow transplant in November 2016. When he was diagnosed, I left my career behind so that I could take good care of him. When the time came for me to go back to work, it occurred to me that I don’t want to do it anymore. I wanted to try something that is a bit more rewarding for me; something that I could do and be able to spend more time at home with the kids. This came up and it was far too appropriate not to apply for it.
What does a day on the job look like?
A big part is consenting ladies on to the program. For that, I go down to the labor wards and speak to ladies before they are going to labor. A lot of them have never heard of it before so I tell them they have these options if they want to donate the placenta to us. I explain where it can be useful and how, if they use the cord blood, it could be a potential stem cell transplant for blood cancer and blood disorders.
A lot of them are really interested in it, but AN only works in four hospitals in the country, so a lot of them have never heard it before. It’s nice to be able to explain all about what happens and where it goes to and, from my point of view, how it could potentially save someone’s life. Every lady I speak to is different; we have such a wide variety of patients from all different backgrounds and countries, so you have to approach each one differently.
We then monitor all the ladies on the ward who have consented. If they go for a cesarean section, we go into theatre with them to collect the placentas soon as it’s delivered, and we can do the necessary processing procedures in theatre. If they deliver naturally in one of the rooms, we give the midwife the collection box then we take that to the lab upstairs and do the procedures there. We try and get it as quickly as we can before it goes cold and before the blood starts clotting.
Has your work with AN helped your family process your experience with Noah?
Without a doubt. Even when I walk into work, it’s the same hospital where Noah actually had his transplant. I often take a long way around and walk past Noah’s ward where he used to be. When you leave the hospital, you look back and, because what happened there was really bad, you are thinking all the negative thoughts. It’s nice to know that I can completely turn it around and just look at all of it as a positive.
Do you ever have to persuade people to bank?
That can be quite tricky. We are told not to coerce anybody into doing anything that they are not sure that they want to do. We just focus on all the positives; yes, you could potentially save someone’s life and, if you don’t bank it, it’s only going to get thrown into the drain.
What do you hope the future will hold for cord blood banking?
At the moment it’s only four hospitals in the country that do it. People ask, ‘why can’t we do this in the more hospitals’, but AN in a charity and it’s not possible to run out at every hospital because of the costs. Banking enough cord blood for every potential patient in the world who is going to possibly going to need seems like quite a tall order to me. It would be nice to think that in the future, it’s maybe something that’s possible.
This is such a rewarding job. I would recommend this job to anybody because you don’t feel like you are actually working; it’s a really nice thing.
Learn more about cord blood collection
Please introduce yourself and AN
I am Daniel Gibson, Head of Innovation at the AN Cell Therapy center. I have worked at AN for 10 years in multiple guises from process scientist, R&D Manager and Head of the program, and I am currently leading on Innovation and Commercialization. AN was established in 1974 by Shirley Nolan to try and find a suitably matched donor for her son Anthony. Unfortunately Anthony passed away but that just made Shirley even more determined to ensure other families didn’t have to go through what she did. She was a pioneer in the approach to meeting the needs of patients which still very much resonates with us as an organization today.
The Cord Blood Program was established in 2008 to meet the increasing demands for cord as an alternative to peripheral blood stem cell (PBSC) and bone marrow (BM) in transplantation. Although imported cords are expensive, AN recognized the increasing demand, and aimed to reduce the costs to the NHS and increase accessibility to patients. Cord blood has a greater tolerance resulting in less graft versus host disease (GvHD), helping bridge the gap in unmet need particularly in the black and Asian minority ethnicities at the time. Cord has been used as an alternative to PBSC or BM to treat patients with blood cancer or blood disorders and is a well proven therapy.
To date we have provided nearly 150 cord blood units from transplants. There are also emerging indications and advanced therapy medicinal products (ATMPs) derived from cord blood that broadens the patient impact. We are providing cord blood and tissue as starting material to researcher, pre-clinical and clinical trials.
What are steps between a sample of cord blood being collected and a clinical-grade cell therapy being administered?
Within our program cord blood is collected at four dedicated sites where we have teams of dedicated collectors working 24/7. This dedicated model is the first step in ensuring we collect high quality cords suitable for clinical use and research. The mother will be consented onto the program at some point prior to the delivery or when she arrives in early stage labor. The team will provide all the information the mother needs to make a decision and complete a medical questionnaire.
If all is well after the placenta has been delivered the AN team will take the placenta to a collection area, and collect the umbilical cord blood and a small sample of cord tissue. Although the collection itself can be quite tricky, our model of highly trained and dedicated staff ensures the best possible chance for every collection to be of a standard for clinical use. Once collected the AN team will label all the samples, complete the necessary collection paperwork and store the unit in a blood fridge prior to collection and transport to our processing facility in Nottingham.
The samples are transported in a validated shipping containers to maintain optimal temperature range to preserve the quality prior to assessment and processing. The units are received by our team of scientists who will verify the contents, inspect the integrity and check the completed paperwork. The cord blood sample is weighed to determine a volume and the samples sent into our clean room for initial sampling, which is done via a sterile dock. The total nucleated cells (TNC) and CD34+ content is enumerated and those that meet the criteria of greater than 140x10^7 TNC and greater than 3.2 x10^6 Cd34+ cells are processed for the clinical inventory.
The samples are red blood cell (RBC) and plasma reduced using the Biosafe (GE Healthcare; UK) Sepax system, optimized to recover a high number of TNC. The turnkey closed system provides a final product in 20ml buffy coat product ready for cryopreservation. A final sample is taking for quality control checks and the sample is then cooled to 4°C prior to adding DMSO/Dextran over the period of 10 minutes to achieve a final concentration of 10% DMSO and 1% Dextran.
The sample is cooled to minimize the metabolic activity and preserve cryoprotective capability of the DMSO. Once added the sample is quickly transferred to our controlled rate freezers where they are brought down to -120°C via a validated protocol before being stored at -196°C. The final quality control checks are performed on the final sample which includes TNC count, CD34+ count, viability by 7-amino-actinomycin D (7AAD) and Annexin V (AnnV), and potency by colony forming unit (CFU) assessment.
Bacteriology and virology testing are confirmed from the residual RBC and plasma fractions and HLA typing is performed at the AN H&I labs. Once the tests have been approved, and the medical questionnaires and virology reviewed by a medical officer, the cord blood unit is then listed on the searchable register. It can be several years before a unit is selected so once a unit has been selected we will review the documentation against today’s standards.
If additional tests are required (such as updated virology screening requirements) we will initiate those tests. At the same time we will thaw a small contiguous sample of the stored cord blood unit. We will perform the sample release tests (TNC count, CD34+ count, viability by 7AAD and AnnV, and potency by CFU assessment) to confirm the integrity of the stored unit and its suitability for transplant. All the information can be provided to the transplant center ahead of time to aid to selecting the best possible option for the patient.
An additional segment is used for verification typing to confirm the identity of the HLA is as expected and originally reported. Units are shipped to the transplant center at cryogenic temperatures in cryoshippers, which are validated to maintain their temperature for greater than 7 days. This means we can get the unit anywhere in the world and maintain its integrity.
How do you quality control the sample of cord blood and the finished cell therapy?
As above the quality attributes attributed to good clinical outcome are TNC and CD34+; to a lesser extent the viability and potency have been shown in single center studies to be important quality attributes. It is important to look at the quality of a cord blood unit holistically; balancing the cell content with viability and potency is important to understand whether it is going to perform as expected during the transplant. The critical quality attributes are a key factor to consider emerging therapies.
What role do regulators, such as the MHRA, or payers, such as the NHS, play in the development of the cord blood bank?
For transplantation, cord blood is minimally manipulated so falls under the regulatory remit of the Human Tissue Authority and we have been regulated for the past 10 years. The regulation provide the appropriate framework to ensure the material is collected ethically within the remit of the consent, that our procedure are fit for purpose and the products are safe and effective. The Federation For Accreditation Of Cellular Therapies (FACT)-Netcord further support this, and our accreditation with them demonstrates we are world class and constantly evolve to ensure the highest level of standards are met.
What are the transportation and biopreservation challenges in cord blood-based therapies?
The samples are stored as an off-the-shelf product at cryogenic temperatures. This means we can ship the units on request, meaning the unit is often on site before the patient has started their conditioning regime, which is the best case scenario. As we know, not everything works like that, but having a stored product means we can be responsive and ship quickly, assuming that everything has been tested beforehand. This is something we often encourage transplant centers to do, even if the cord blood unit isn’t their first choice, as it’s always good to have a backup!
As it’s a stored product it is important to assess longevity of the storage. To overcome this, as is a FACT-Netcord standard, we have a stability program to assess the viability and potency of stored products over time.
We are working with a number of researchers who are developing ATMPs from cord blood or tissue; these prove to be a little more challenging as the product is required to be fresh as possible. We have validated shipment containers that can maintain 4-8°C for up to 72 hours and have established agreements with courier companies to deliver within a prescribed time frame. This takes a serious amount of logistics management which our team in Nottingham controls.
The regulations are another important consideration as the movement of samples for human application requires a license and agreement with the end users. We always work closer with users to ensure seamless passage across borders of the therapeutic product but also for research material and starting material for ATMPs.
What are the advantages/benefits of a cell therapy derived from cord blood?
In terms of traditional stem cell transplantation, cord blood has a number of benefits. Firstly it’s a stored product, meaning there is limited donor attrition from the point of listing. The additional tests and confirmation of integrity can be performed early in the selection process, providing peace of mind, and there is a wealth of information available to determine suitability through the critical quality attributes.
As described above cord blood can be responsive; our record so far is 16 hours from the point of request to delivery at a transplant center.
Cord transplant has lower incidence of GvHD due to the naivety and tolerance between maternal/fetal co-existence. If a perfect match cannot be found from adult donor sources then cord is a potential option, as a mismatch is more permissible. The diversity of cord banks (through deliberate placement of collection sites like ours) can be more responsive to population changes. For example, it is projected that the ‘mixed ethnicities’, currently the smallest of the minority group, will become the largest representation of the minority group within the next 10 years. This could mean finding donors for younger patients becomes more difficult which has been reported as true from some registries. Cord blood banks can be responsive to changes like this.
From a traditional transplant setting, the quality requirements for transplant are very high requiring a high TNC dose to overcome a delay in engraftment. The TNC dose is a limiting factor in cord but early trials show promise for cord expansion. Units that do not make the clinical threshold are available for research. We are also research tissue banks, utilizing and facilitating research through that arm. From the non-traditional setting, a benefit for using cord in cell therapy is the material is readily available (and collected through well-established protocols, regulated by the HTA and accredited by FACT Netcord) meaning scalability into and beyond clinical trials is relatively easy. We are currently supplying the starting material for pre-clinical and clinical trials for a number of ATMPS.
Finally, cord is really interesting and has unique capabilities; I don’t believe we have fully evaluated its full potential. Cord has proven to be a valuable source for regenerative medicine, a number of studies reporting early stage trial data is very promising.
What changes have you noticed in cord blood banking in the last decade?
Clinical conversion rates have decreased with the increase in delayed cord clamping. This is a challenge to maintaining high quality clinical cords for transplantation although there are a lot of emerging areas where the cell count may not be so limiting.
We note a reduction in double cord transplants; several years ago transplanting two cords to meet cell dose requirements for a larger patient would have been common place. However, with improved survival data, conditioning regimes and post-transplant care, comparable survival rates can be achieved with single cord transplants.
There have been numerous improvements to cell processing systems, meaning we can provide a better defined final product, which means there is greater availability of high quality cords.
Quality assessment and standardization of protocols has improved over the past years which has allowed for better selection. The lessons learnt in defining and qualifying cord as a cellular therapy are important as we look towards advanced therapies that will be developed to be off-the-shelf, rigorously qualified and regulated. We have started to see more efforts in bridging the gap of understanding between the cell providers and the cell users. Finally one of the biggest drivers of change over the last 10 years is research – there has been a lot investment into cord expansion and new emerging therapies which we are starting to see come to fruition.
What are your predictions for the next 10 years?
For traditional transplantation I believe cord will be a valuable donor source with an ever changing demographic. Europe has seen a lot of immigration in recent years which provide unique demographics with unique patient needs. However as the populations change with naturalization, and second and third generation mixing, the subsequent patient cohorts present with their own unique donor counterparts. This is where cord will be of value to continue to meet these needs.
There has been an explosion in the field and I am sure precision medicine will become a reality in the next 10 years. There are a lot of hurdles to overcome and we have to rethink our approach to patient diagnosis, identifying the best treatment option for them, the logistics and deliver of advanced therapies and the data/surveillance of bespoke treatments. I hope to see technology rapidly change to respond to the need to analyze big data.