Singapore, 21 May 2018

A multi-disciplinary team of researchers from the National Cancer Centre Singapore (NCCS), the National University of Singapore (NUS), Duke-NUS Medical School (Duke-NUS) and Singapore General Hospital (SGH) has developed a novel method to expand the blood-forming stem cells in umbilical cord blood. Adult patients suffering from blood malignancies require sufficiently high cell numbers for rapid recovery.

This efficient, speedy and potentially cost effective technique addresses that current clinical challenge, thereby opening doors for more patients to benefit from umbilical cord blood transplants. 

The work was published in the journal Stem Cells Translational Medicine in May 2018.

Limitations in current treatments for blood malignancies

Blood cancers and several metabolic and immune disorders are typically treated through bone marrow or by peripheral blood stem cells transplantation as a source of haematopoietic (blood) stem cells. These types of stem cells are able to give rise to blood cells which are critical to the survival of patients. However, bone marrow transplantation is highly invasive for the donor, and faces the difficulty of finding a right match between donor and recipient, while peripheral blood stem cells transplantation is associated with increased rates of disease relapse and post-transplant complications. 

In recent years, an effective alternative to bone marrow as a source of haematopoietic stem cells is the use of umbilical cord blood. An advantage of umbilical cord blood over live donor registry sourced bone marrow or peripheral blood is the ease of access as these clinical-grade cord blood units have been tested for infectious disease. The tested blood is then cryopreserved, or preserved at a very low temperature. . With over 800,000 units of umbilical cord blood stored in over 50 public cord blood banks worldwide, the information for which could easily accessed via international registries. Concurrently, there are close to 100 private cord blood banks worldwide, with over 4.5 million units primarily for usage by the baby, family or relatives in future. In addition umbilical cord blood transplants have a lower risk of rejection and thus pose less risk for patients, and have been shown to give equivalent outcomes to fully matched bone marrow transplants. 

Furthermore, umbilical cord blood grafts require a less stringent criteria for matching between donor and recipient when compared to bone marrow or mobilised peripheral blood stem cells. This allows transplants for individuals from ethnic minorities and inter-racial backgrounds. This advantage is even more pertinent for the Asian countries due to small family nucleus and nascent bone marrow registries. Given that transplant centres across Asia are still developing, cord blood transplantation are likely easier to perform with 30 years of clinical experience coupled with lesser post-transplant complications compared to upcoming technologies such as haplo-identical transplantation. In recent studies carried out in USA, it has been shown that cord blood transplantation gives better clinical outcomes in patients who have poor disease status when compared to conventional bone marrow or peripheral blood stem cells. 

However, despite the benefits of using umbilical cord blood stem cells for transplantation, its clinical use is constrained by the low number of total nucleated cells (TNC) and haematopoietic stem and progenitor cells (HSPC) present. For umbilical cord blood transplants to be successful, there should be at least 30 million cells per kilogramme of the recipient’s body weight.  Based on this cell dose requirement, it is estimated that that the utility of up to 40% and more than 80% of cord blood units stored in the public and private banks, respectively, could benefit patients should the Singapore-developed stem cell expansion technologies be successfully established in the near future.

Innovative method to expand stem cells

Recognising that high cell numbers are essential for rapid patient recovery and reduction of mortality, a chemical substance that can expand TNC and HSPC numbers in umbilical cord blood was identified by Associate Professor William Hwang and his team in Duke-NUS and SGH, by screening a library of compounds designed and synthesized by Professor Christina Chai and her team from the Department of Pharmacy at the NUS Faculty of Science. These compounds were originally developed by Prof Chai for stem cell differentiation studies. On the other hand, Assoc Professor Hwang’s translational research laboratory focuses on growing blood stem cells and has successfully developed several clinical trials.  The small molecule, coined C7, is considered highly significant in the context of improving clinical outcomes. 

The collaboration

This project is the result of a fruitful collaboration spearheaded by Associate Professor Hwang, along with medicinal chemist Prof Chai, and nano-technology based drug delivery specialist Associate Professor Gigi Chiu from the NUS Department of Pharmacy. Assoc Prof Hwang is the Medical Director of NCCS, and part of the Cancer and Stem cell Biology Programme at Duke-NUS Medical School. He is a clinician-scientist and a haematologist by training. The senior researchers combined their expertise to discover and develop this novel stem cell expansion technology. They were supported by Dr Sudipto Bari and Dr Zhong Qixing, who conducted the studies as part of their doctoral research. Dr Bari was under the supervision of Assoc Prof Hwang and Assoc Prof Chiu, while Dr Zhong was under the supervision of Prof Chai. Both Dr Bari and Dr Zhong recently received their Doctor of Philosophy degree from the NUS Department of Pharmacy. 

The invention is jointly owned by Duke-NUS and SingHealth and is being commercialised through the Joint Centre for Technology Development, a Centre managed by both institutions. 

While several research teams have worked on the clinical-scale expansion of umbilical cord blood stem cells, this is the first to be primarily developed and patented in Singapore. The addition of the proprietary chemical substance C7 was able to achieve a significantly higher number of HSPC within a shorter duration with the need to add lesser number of biological promoters. The umbilical cord blood cells required lesser upstream processing to enable expansion using C7 when compared to other known compounds.   

Impact in clinical outcomes

The team’s discovery has potential significant impact in clinical settings. To date, over 40,000 umbilical cord blood transplants have been carried out to treat haematological malignancies, which accounts for 3,000 umbilical cord blood transplants per year worldwide. However, if there are sufficient umbilical cord blood units that have cell doses of more than 1.2 billion cells, it is estimated that another additional 9,000 patients could benefit from umbilical cord blood transplants per year worldwide. Currently, clinicians are hard pressed to choose cord blood units that have higher cell number over the degree of match that exists between donor and recipient to ensure successful transplant outcome. However, expansion technologies such as this will allow physicians to choose units that have a higher degree of matching between donor and recipient, thereby reducing both post-transplant complications and its associated medical costs. Expansion technologies also make available a larger proportion of the cryopreserved inventory to the patients. 

“Although these are early days, we are very excited over the possibilities that our technology can offer. This work is a great example of how a team can achieve so much more than the individual. The medicinal chemists provide the compound, the biologists assess the potential of the compound, and the clinician-scientist brings the discovery from bench to potential bedside,” said Prof Chai, Head of the NUS Department of Pharmacy, who is one of the Co-Principal Investigators of this project.

“There are patients who are unable to find a fully matched bone marrow or peripheral blood stem cells. For these patients, umbilical cord blood is the only source of grafts. However when such patients find an umbilical cord blood graft, they may not undergo the transplantation due to the low cell numbers. Expanded umbilical cord blood would be a life-saving option. We are grateful for the public research grants from various organisations and to the volunteer donors of umbilical cord blood through the Singapore Cord Blood Bank that have allowed us to conduct in-depth research on cell expansion which could potentially bring hope to these patients,” said Assoc Prof Hwang who is also a Senior Consultant with the Department of Haematology, SGH.

The team has been awarded an Innovation and an Ignition grant from the Singapore-MIT Alliance for Research and Technology (SMART) as well as an Innovation to Develop grant from the National Health Innovation Centre (NHIC). The current study was conducted through the funding from SMART while the NHIC funding would be used to conduct pre-clinical manufacturing and testing from March 2018 to February 2019. Clinical trials are targeted to start in mid-2019 with it being led by clinicians from SGH.

National Cancer Centre Singapore (NCCS) provides a holistic and multi-disciplinary approach to cancer treatment and patient care. We treat almost 70 per cent of the public sector oncology cases, and they are benefiting from the sub-specialisation of our clinical oncologists. To deliver among the best in cancer treatment and care, our clinicians work closely with our scientists who conduct robust cutting-edge clinical and translational research programmes which are internationally recognised.  NCCS strives to be a global leading cancer centre, and shares its expertise and knowledge by offering training to local and overseas medical professionals. www.nccs.com.sg

A leading global university centred in Asia, the National University of Singapore (NUS) is Singapore’s flagship university, which offers a global approach to education and research, with a focus on Asian perspectives and expertise. 

 

NUS has 17 Faculties and Schools across three campuses. Its transformative education includes a broad-based curriculum underscored by multidisciplinary courses and cross-faculty enrichment. Over 38,000 students from 100 countries enrich the community with their diverse social and cultural perspectives. NUS also strives to create a supportive and innovative environment to promote creative enterprise within its community.  

 

NUS takes an integrated and multidisciplinary approach to research, working with partners from industry, government and academia, to address crucial and complex issues relevant to Asia and the world. Researchers in NUS’ Faculties and Schools, 30 university-level research institutes and centres, and Research Centres of Excellence cover a wide range of themes including: energy, environmental and urban sustainability; treatment and prevention of diseases common among Asians; active ageing; advanced materials; risk management and resilience of financial systems. The University’s latest research focus is to use data science, operations research and cybersecurity to support Singapore's Smart Nation initiative. 

For more information on NUS, please visit www.nus.edu.sg. 

The Duke-NUS Medical School (Duke-NUS) was established in 2005 as a strategic collaboration between the Duke University School of Medicine, located in North Carolina, USA, and the National University of Singapore (NUS). Duke-NUS offers a graduate-entry, four-year MD (Doctor of Medicine) training programme based on the unique Duke model of education, with one year dedicated to independent study and research projects of a basic science or clinical nature. Duke-NUS also offers MD/PhD and PhD programmes. Duke-NUS has five Signature Research Programmes: Cancer and Stem Cell Biology, Neuroscience and Behavioural Disorders, Emerging Infectious Diseases, Cardiovascular and Metabolic Disorders, and Health Services and Systems Research. 

The Centre for Technology and Development (CTeD), established in 2013 at Duke-NUS, creates value by partnering with organisations, researchers and innovators to nurture and develop Duke-NUS technologies and intellectual property into commercial entities and products.

 

For more information, please visit www.duke-nus.edu.sg.

The Joint Centre for Technology and Development (J-CTeD) is a partnership between the Centre for Technology and Development at Duke-NUS and SingHealth Office of Intellectual Property to commercialise jointly owned IP.

Singapore General Hospital, a member of Singapore Health Services, is the public sector's flagship hospital. Established in 1821, SGH is Singapore's largest acute tertiary hospital with 1,700 beds and national referral centre offering a comprehensive range of 39 clinical specialties on its campus. Every year, about 1 million Singaporeans benefit from advanced medical care delivered by its 800 specialists. As an academic healthcare institution and the bedrock of medical education, SGH plays a key role in nurturing doctors, nurses and allied health professionals, and is committed to innovative translational and clinical research in her continual strive to provide the best care and outcomes to her patients. www.sgh.com.sg

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