Studies Supported by the Cord Blood for Research Program

‘Characterizing leukemia interactions with the immune system to identify novel therapies for relapsed/refractory disease’

Project Location: Toronto

Estimated Project Start Date: 2022-07-01

Estimated number of cord blood units required to complete this research project: 12

Leukemia is a common and devastating pediatric and adult malignancy. Novel treatments for a subset of patients with relapsed/refractory T cell disease are almost non-existent. Unlike patients with B cell leukemia who have benefitted from immune system targeted therapies, these treatments are still unavailable to patients with T cell leukemia. We hypothesize that, similar to other cancers, leukemic T cells suppress anti-tumor immune responses in diseased tissue, including the bone marrow, the tissue that generates healthy blood and immune cells. Our lab is performing single-cell RNA-sequencing of healthy and diseased bone marrow to identify how T cell leukemia interacts with immune cells in this tissue. We found that immune cells from diseased, but not healthy, bone marrow express markers of immune exhaustion suggesting that leukemic cells are suppressing an anti-tumor immune response. Additionally, we identified several immunosuppressive ligands upregulated on leukemic cells that are known immunotherapy targets in other cancers. Next, we plan to interrogate expression of T cell exhaustion markers, such as LAG3 and CTLA4, on T cells from healthy donor and primary T-ALL blood samples, as well as immunosuppressive ligands on healthy donor blood and CD34+ hematopoietic stem cells. This analysis will allow us to determine if markers of immune exhaustion are found on circulating immune cells from leukemia patients. Furthermore, analysis of immunosuppressive ligand expression on CD34+ hematopoietic stem cells will allow us to identify the potential for on-target off-cancer effects of immunotherapies. Identification of markers of immune exhaustion on blood immune cells from leukemia patients but not CBS donor healthy immune cells could provide valuable diagnostic information concerning the immunosuppressive landscape of the bone marrow in leukemia patients. This study will characterize the leukemia immune microenvironment and identify targets for immunotherapeutic intervention for patients with treatment refractory leukemia to improve outcomes. Our research seeks to identify new immune cell therapies for children and adults with leukemia. Our work is in line with the blood products for research goal of providing primary samples for investigators to promote advances in the field of cellular therapy.

'Optimization of Regulatory NK cell expansion for therapy of cGvHD'

Project Location: Vancouver
Estimated Project Start Date: 2020-11-01
Estimated number of cord blood units required to complete this research project: 24

Hematopoietic Stem Cell Transplantation (HSCT) is a critical immune-based therapeutic option for patients with high-risk and relapsed blood cancers. However, HSCT is attributed to an increased risk of complications, the most severe being chronic graft-versus-host-disease (cGvHD), in which foreign donor immune cells attack the recipient’s tissues. cGvHD occurs in 25% of pediatric and 60% of adult HSCT survivors. It is known to cause chronic organ damage and has a 10-25% mortality rate.

Our team has identified a cGvHD biomarker (non-cytolytic CD56bright Natural Killer population (NKreg)) closely correlated with an inhibition of cGvHD. Further, the adoptive transfer of expanded cytolytic NK cells has shown to potentially decrease leukemia relapse with no increase in GvHD. Thus, we hypothesize that the adoptive transfer of expanded NKreg cells after HSCT represents a significant strategy to decrease cGvHD without increasing leukemia relapse.

In completion of the proposed research, we expect to understand the characteristics of CD56bright NKreg cells that associate with no development of cGvHD and establish an optimal expansion protocol. These approaches will provide a biological understanding for developing strategies to augment NKreg cells as an adoptive transfer therapy for cGvHD, significantly contributing to the goal of improving the safety and efficacy of HSCT.

Generating antibody producing B cells in a dish

Project Location: Vancouver
Estimated project start date: 2021-07-06
Estimated number of cord blood units required to complete this research project: 180

Immune cells play an important part in fighting and eliminating infections. Specialized immune cells, called B cells, are a powerful tool used by the body to recognize foreign invaders such as germs and mark them for elimination. These markers are called antibodies, and can be secreted by B cells (called plasma cells) at a rate of thousands per second. Plasma cells can also remain on stand-by for decades until the same invader is encountered, which helps eliminate infections more quickly and efficiently.

To date very little is known on how to produce B cells in a laboratory dish starting from hematopoietic stem/progenitor cells (HSPCs) such as those found in cord-blood. To date, few studies have reported generating B cells from human HSPCs, all of which are relatively inefficient and rely on animal cells to support their development. The aim of our study is to use HSPCs to efficiently generate B cells without the use of animal-based materials, and further mature these cells to plasma cells. Knowledge of this could serve as a powerful tool for researchers to grow plasma cells from their own HSPCs, to one day allow plasma cells to be used as cell therapeutics in hospitals around the world.

Studying the genes controlled by MTF2 in blood cells

Project Location: Ottawa

Estimated Project Start Date: 2020-10-01

Estimated number of cord blood unites required to complete this research project: 6

The goal of our research is to understand the role of MTF2 in blood cells. MTF2 is part of a protein complex that controls whether of some genes are turned on of off in blood cells. When MTF2 is not properly functioning in leukemia cells, we discovered that it is not able to properly control the expression certain genes. This results in genes being abnormally turned on, which in turn prevents the leukemia cells from responding to chemotherapy treatment. Using cord blood cells obtained from CBS, we demonstrated that using drugs to block a gene called MDM2, which is abnormally turned on, can help leukemia cells respond to chemotherapy. This idea is being tested in a clinical trial to help leukemia patients respond better to standard chemotherapy.

We will continue to characterize the genes controlled by MTF2 to understand the function of the genes in blood cell development and leukemia. The results of these studies will advance our knowledge about the normal and abnormal development of blood cells that may be applied to developing new effective therapies to treat leukemia.

Evaluation of CD71+ cells in stored red blood cell concentrates

Project Location: Edmonton

Estimated Project Start Date: 2020-10-01

Estimated number of cord blood unites required to complete this research project: 6

Lay Summary of the Research Project: Red blood cell (RBCs) product quality can differ due to the age and sex of the blood donor. We proposed that young female blood donors have a higher proportion of “young” circulating red blood cells which have unique physical characteristics. In our CBS funded project we are examining the unique properties of the young RBCs that are enriched in female blood donors and how these cells survive and function following separation into defined red blood cell products used for transfusion. We are specifically interested in the ability of a specific immature subtype of RBCs have on recipients. As these cells are extremely rare in circulation, we need to establish very sensitive analytical methods to detect and count them. To develop this test, we need access to samples with an enriched number of these cells. Cord blood has a large number of these immature RBCs and is therefor an excellent source for our assay development work. Using donated cord blood samples we will establish our test method’s limit of detection, linearity and precision which is critical to us being able to measure these cells in blood donor samples.

An automated manufacturing solution for expansion of blood stem cells

Project Location: Toronto

Estimated Project Start Date: 2018-07-01

Estimated number of cord blood units required to complete this research project: 30

Lay Summary of the Research Project:
Umbilical cord blood has been proven to be a valuable source of blood stem cells for transplantation to treat blood disease and cancer. In order for these cells to be available in sufficient quantities, they can be expanded in culture, outside of the body. By increasing the number of stem cells, each umbilical cord blood unit is made more clinically efficacious. We are developing an automation solution to make this expansion process more robust and reproducible. This will enable these cells to be used in large scale clinical trials and ultimately for commercial scale production of this therapy. 

Hematopoietic stem cells and transfusion medicine

Project Location: Ottawa

Estimated Project Start Date: 2018-08-01

Estimated number of cord blood units required to complete this research project: 125

Lay Summary of the Research Project:
Umbilical cord blood units are a source of hematopoietic stem cells used for transplant in patient without a suitable donor. Collection, processing, and storage under freeze are steps involved in cord blood banking. The impact of these processes on hematopoietic stem cell quality and activity need to be investigated to optimize the quality of the cord blood graft distributed by the Canadian Blood Services. Our projects investigate the impact of processing on cord blood quality and potency, investigate the impact that expansion of the graft has on the its quality and finally test new additive solution to improve the recovery of the graft after freeze. Improved quality will translate into improved activity which will reduce issues in patients and hasten their recovery

Regulatory T cells from discarded human thymus for adoptive cell immunotherapy: moving garbage to gold

Project Location: Edmonton

Estimated Project Start Date: 2018-03-01

Estimated number of cord blood units required to complete this research project: 22

Lay Summary of the Research Project:
Patients who received transplant or those with autoimmune diseases often need lifelong treatment with drugs that suppress the immune system. In this regard, special immune cells called ‘regulatory T cells’ (or ‘Tregs’) are of enormous interest because they naturally suppress immune responses. The use of Tregs as a cellular therapy to treat a variety of immune disorders, including diabetes and transplant rejection is currently being explored. In this project, we will develop standard laboratory protocols for isolation, expansion and storage of thymic Tregs. We will test whether these Tregs can suppress immune responses effectively. If so, our work will allow direct clinical testing of thymic Tregs as an “off-the-shelf” therapy. We expect to demonstrate that discarded human thymus is a superior source of therapeutic Tregs that can be moved forward to clinical testing.

Cell-based therapy for experimental acute kidney injury

Project Location: Ottawa

Estimated Project Start Date: 2018-02-01

Estimated number of cord blood units required to complete this research project: 36

Lay Summary of the Research Project:
Acute kidney injury (AKI) is a serious condition in which kidney function falls rapidly, often due to loss of blood flow. AKI affects about one out of every twenty people in hospital, and mortality is high. Unfortunately, there are no treatments to improve kidney repair after AKI. Use of stem cells may help kidneys recover from AKI. Recently, we isolated “progenitor” cells from human umbilical cord blood and infused them into mice with AKI caused by temporary blockage of blood flow to the kidneys. The cells reduce kidney damage, and appeared to release factors that stimulated recovery. In fact, the cells shed tiny membrane particles (“exosomes”) that contain a protective substance called “miR-486-5p”. Our proposal represents the critical next step in developing cord blood-derived exosome treatments that could help humans with AKI

Study of immuno-therapeutics anti-tumor efficacy in humanized mice

Project Location: Toronto

Estimated Project Start Date: 2018-02-01

Estimated number of cord blood units required to complete this research project: 24

Lay Summary of the Research Project:
Immunotherapeutic antibodies have been used to treat some cancer patients successfully through boosting the patients’ own immune system. However, scientists are increasingly aware of the complexity of this type of therapy and of the urgent need for developing next-generation antibodies with better efficacy. Therefore, we have generated some next generation immuno-therapeutic antibodies. We will use cord blood as a source to purify hematopoietic stem cells (HSC) and then generate humanized mice. We will use humanized mice as a model system to assess our immunotherapeutic Abs anti-tumor efficacy and advance them to clinical trials

Stem Cells of the musculoskeletal system: An epigenetics study from childhood to adulthood

Project Location: Ottawa

Estimated Project Start Date: 2018-01-15

Estimated number of cord blood units required to complete this research project: 54

Lay Summary of the Research Project:
Sarcopenia is the age-related loss of muscle mass that occurs when the muscle stem cells fail to meet the regenerative demands leading to muscle atrophy. Past research in mice has demonstrated that there are differences in which genes are active in young individuals compared to older individuals, particularly in muscle regeneration. In this project, we will use adult stem cells (including hematopoietic stem cells from cord blood) isolated from human biopsies to identify and characterize the epigenetic changes that contribute to the progression of age-related muscle wasting. Successful completion of this project is expected to help identify genes that can be targeted in certain diseases and aging processes.  

Characterization of post-thaw recovery of cord blood progenitors cryopreserved with novel recrystallization inhibitors

Project Location:  Ottawa

Estimated Project Start Date: 2015-12-18

Estimated number of cord blood units required to complete this research project: 20

Lay Summary of the Research Project:
Umbilical cord blood is a rich source of stem and progenitor cells with current and future applications in regenerative medicine. The national public cord blood bank (NPCBB) collects and stores cord blood units for future stem cell transplantation. Cryopreservation is the storage of biological products at temperatures below -180 degrees Celsius. The current standard for cord blood banking is to cryopreserve cord blood units with 10% DMSO. However, DMSO is associated with a number of toxic effects. Given that the majority of cellular injury during cryopreservation is a direct result of ice growth, we hypothesize that our novel small molecule ice recrystallization inhibitors will minimize the cellular damage associated with ice growth and will result in improved cord blood unit functionality when thawed.

Application of human NK cell therapy and the use of humanized mice to study prevention and treatment against cancer

Project Location:  Hamilton

Estimated Project Start Date: 2016-01-05

Estimated number of cord blood units required to complete this research project: 120

Lay Summary of the Research Project:
Until recently, responses of the human immune system to human cancers and human specific infections, such as Hepatitis C virus, were not possible to study in a mouse model. The goal of our research is to use cord blood stem cells isolated from umbilical cord blood to generate "humanized mice" which have a functional human immune system. This gives us the ability to investigate how our immune system works in a living system, against a variety of diseases which are impossible to examine at this level in humans. We aim to study both cancers, such as breast cancer and infections, such as Hepatitis C virus. Through a cell culture method established in our lab, we can produce a large number of immune system cells from a small cord blood sample. These immune cells can then be used to treat humanized mice with either tumors or infection. Ultimately, through cord blood donation, we will be able to generate humanized mice and apply what we learn to create more effective treatments to fight breast cancer and viral infection.

Effects of radiation on cord blood-derived stem cells

Project Location: Chalk River

Expected Project Start Date: 2015-09-01

Estimated number of cord blood units required to complete this research project: 30

Lay Summary of the Research Project:
Patients with hematological cancers often undergo stem cell transplantation that requires high dose chemo- or radio-therapy to kill all resident leukemic cells followed by transplantation of blood stem cells from a healthy donor. Unfortunately, 50% of patients undergoing this therapy still succumb to the disease due to leukemia re-emergence (leukemia relapse). One of the hypotheses for leukemia relapse is the existence of leukemic cells that are resistant to chemo-/radio-treatment. However, recent studies have shown that low doses of radiation can induce biological effects that promote cancer cell destruction. We propose to study whether low doses of radiation given to patients prior to chemo-/radio-therapy and stem cell transplantation can promote better leukemia cell destruction. This approach may greatly improve the outcomes of transplantation therapy and prevent future leukemia relapse. Importantly, these studies require the use of human blood stem cells and cord blood is a rich source of these cells.

Development and validation of a humanized mouse model for the pre-clinical evaluation of vaccines against liver pathogens

Project Location: Edmonton

Expected Project Start Date: 2015-03-17

Estimated number of cord blood units required to complete this research project: 25

Lay Summary of the Research Project:
Malaria is responsible for nearly 1.24 million deaths annually, mostly young children in sub-Saharan Africa. Despite decades of research, a vaccine to prevent malaria remains elusive.  One of the major challenges in vaccine development is lack of suitable animal models to evaluate new experimental vaccines.  Chimpanzees and other primates are not available for either ethical or financial reason and there is currently no way to test vaccines in mice against the human species of parasites. In order to overcome some of these obstacles, we will develop a mouse transplanted with a human liver and a human immune system established from cord blood. We will use these mice to test new experimental malaria vaccines. The ability to optimize the delivery of the vaccine in mice prior to embarking on expensive human trials will enable the rapid early phase development of promising vaccines against malaria and other pathogens that infect the liver.

Cell production augmentation techniques

Project Location: Kingston

Expected Project Start Date: 2015-03-01

Estimated number of cord blood units required to complete this research project: 20

Lay Summary of the Research Project:
Regenerative medicine involving the transplantation of cells holds great promise for improving the clinical efficacy of conventional treatments. This is possible because the implantation of repair-specific cells (such as stem cells from cord blood) have the ability to restore tissue to normal function. The current procedures to create cell-based products are all manual in nature and hence do not enable high reproducibility and cost-effectiveness. Automated production could potentially be achieved through the robotic duplication of manual actions; however, the general industry challenge is that existing robotic systems for basic cell culture are highly complex, require significant space for operation, and require a high capital equipment investment. We are investigating cell parameters and system requirements to develop an innovative, cost-effective and automated bioreactor-based system to meet the clinical production challenges related to cord blood expansion in order to provide more options for patient transplant.

Strategies for enhancing cell therapy for optimal regeneration in pulmonary arterial hypertension – SECTOR-PAH

Project Location: Ottawa

Expected Project Start Date: 2014-11-28

Estimated number of cord blood units required to complete this research project: 200

Lay Summary of the Research Project:
Pulmonary arterial hypertension (PAH) is a devastating disease in which high blood pressures in the lung lead to heart failure and eventually death. Emerging regenerative therapies involving endothelial progenitor cells (EPCs) have begun to show some promise in clinical trials. Although EPCs are typically rare in circulating blood, we now know that they are more abundant in cord blood and may also be even more efficient at cardiovascular repair. We intend to use cord blood to efficiently generate EPCs and perform studies so that we may better understand why they are effective in PAH. With a better understanding of their mechanisms, we aim to develop methods to further enhance the activity EPCs to design more effective therapies for cardiovascular diseases such as PAH.

Ex Vivo Differentiation of Human Hematopoietic and Endothelial Progenitor Cells for Genomics and Proteomics Analyses

Project Location: Ottawa

Expected Project Start Date: 2014-08-05

Estimated number of cord blood units required to complete this research project: 300

Lay Summary of the Research Project:
Cord blood is a rich source of blood stem cells. These cells are currently used therapeutically in patients with beta-thalassemia, leukemia, limb ischemia, myocardial infarction and stroke. However, blood stem cells cannot be isolated in sufficient quantities to treat adults and cannot be expanded in the laboratory. Furthermore, there is room to improve their efficiency in repairing diseased tissue.

Our laboratory is using innovative technologies to decipher the role of specific proteins that control the function of blood stem cells. This will allow us to identify specific drugs to ameliorate the ability of these cells to treat disease. We anticipate that our study will lead to the development of new strategies to 1) expand blood stem cells in the laboratory such that enough cells can be produced to treat adults; and 2) improve the function of blood stem cells such that they are more efficient in repairing damaged blood vessels.

Evaluation of culture media for cord blood-derived progenitor cells

Project Location: Vancouver

Expected Project Start Date: 2014-08-05

Estimated number of cord blood units required to complete this research project: 20

Lay Summary of the Research Project:
A set of blood-derived progenitor cells could be useful for the treatment of diseases as diverse as vascular disease, stroke, cancer, and diabetes. However, these circulating cells are extremely rare, and must be cultured (grown in medium) to expand their numbers before use. We are evaluating several cell culture media for the isolation and expansion cord blood-derived progenitor cells, which could be useful in the future in human cell therapy.

Elucidating the role of PCL2 in normal hematopoiesis and leukemogenesis

Project Location: Ottawa

Expected Project Start Date: 2014-08-20

Estimated number of cord blood units required to complete this research project: 75

Lay Summary of the Research Project:
Acute Myeloid Leukemia (AML) is one of the deadliest types of cancers. 30-40% of AML patients younger than 60 years of age are long-term survivors, while only 10-15% of patients over 60 years of age are long-term survivors. Less than 10% of patients with relapsed AML survive long-term. The standard treatment has not changed in over 30 years, which is why survival rates have not improved. We recently identified a protein called PCL2, which is abnormally expressed in most AML patients. We believe that PCL2 could be a target for new chemotherapeutic drugs to treat AML patients that harbour PCL2 mutations. To pursue this strategy, we need to understand the role of PCL2 in normal and leukemic blood development. Therefore we will manipulate the expression of PCL2 in umbilical cord blood cells to help us understand the role of PCL2 with the ultimate goal of developing better therapies for AML.

Developing bioprocesses to expand cord blood hematopoietic stem cells for clinical use

Project Location: Toronto

Expected Project Start Date: 2014-09-10

Estimated number of cord blood units required to complete this research project: 540

Lay Summary of the Research Project:
Hematopoietic stem cell (HSC) transplantation is the only stem cell therapy routinely performed in patients with leukemia and lymphoma. However 40% of patients will not find a suitable bone marrow donor. Using umbilical cord blood (UCB) as an alternative source of HSCs has several advantages, including non-invasiveness, ready availability, and a higher tolerance for HLA mismatches. The limited number of stem and progenitor cells in a single UCB unit has impaired the success rate of UCB transplants. Our lab has developed an automated closed-system bioprocess that robustly expands UCB-derived HSCs and progenitors. Our next steps involve the use of a novel small molecule and integrating the detection system into the bioreactor to automate media injection, both of which will maximize the expansion of stem cells and enable the real-time control of the UCB cell culture in a sample-specific manner while minimizing the media use and the associated cost.

Characterization of the hematopoietic reconstitution enhancing activity of osteoblasts derived from human mesenchymal stromal cells

Project Location: Ottawa

Expected Project Start Date: 2014-09-22

Estimated number of cord blood units required to complete this research project: 75

Lay Summary of the Research Project:
Umbilical cord blood transplantation provides the opportunity for patients without a suitable donor to receive a life-saving stem cell transplantation. This procedure is however associated with a slower recovery of blood cells. Cord blood stem cells can be expanded in culture, and these have been shown to be able to produce blood cells faster. In this proposal, we will investigate how bone marrow cells regulate the growth of cord blood stem cells. We will also try to identify molecules that are responsible for these activities. This research will foster new knowledge on the role of bone cells as important regulators of blood cell production, and may lead to new solutions to improve cord blood transplantation. Indeed, new approaches are urgently needed to address the needs of the increasing number of Canadian patients who will soon rely on UCB transplantation for their continuing health.

Study of immune-based treatments for cancer using mouse models with human immune systems and tumors

Project Location: Princess Margaret Cancer Centre/University Health Network, Department of Medical Oncology & Hematology

Expected Project Start Date: 2019-11-08

Estimated number of cord blood units required to complete this research project:  5

Lay Summary of the Research Project:
Lung cancer is the leading cause of cancer-related death. Immunotherapy uses a patients own immune system to control and eliminate cancer cells. Immunotherapy represents one of the most promising avenues to produce durable benefit from treatment and long-term survival in lung cancer patients. However, the biology underpinning response to immunotherapy remains poorly understood and the mechanisms that allow certain patient's tumors to resist immunotherapy are similarly poorly characterized. A major barrier to furthering our understanding of the biology of immunotherapy in lung cancer is the lack of experimental models that can effectively replicate the complex interactions between cancer cells and the immune system that underpin the activity of immune checkpoint inhibitors. Our proposed study utilizes a novel mouse model where a human immune system is recreated using blood stem cells and then a human tumor implanted in order to study the interactions between human immune cells and tumor cells. The ultimate goal of this project will be to better understand the reasons that certain tumors respond or resist immunotherapy and identify new approaches to immunotherapy that may benefit cancer patients. The findings of this study will also potentially allow the development of new immunotherapies based around the use of cord blood cellular therapy.

3D Bone Marrow Tissue Engineering for HSC Regenerative Medicine

Project Location: York University, Mechanical Engineering, Toronto, ON

Expected Project Start Date: 2019-04-01

Estimated number of cord blood units required to complete this research project: 10

Experimentation with HSC and progenitors (HSPC) is challenging. When removed from their native bone marrow niche and place in vitro, HSC and Progenitor (HSPC) cells very quickly (24-72h) lose their function. Mounting evidence suggests that the bone marrow extracellular matrix (ECM) is a critical, yet underappreciated, component of the niche that may be instructive to stem cell regulation. This research aims to develop technology that discovers in vitro niche conditions and applies this knowledge to elucidate niche interactions.

In the long term, this research can lead to the development of readily available tissue-matched engineered bone marrow tissue to be used for transplantation. Canadian bone marrow transplant patients stand to benefit the most with shorter waiting times. Canadian healthcare savings can also be realized by quickly treating patients and removing them from ever-lengthening transplant waiting list and associated healthcare costs in managing sick waiting patients. Furthermore, this research can be applied to test new experimental drugs that unintentionally cause myelosuppression toxicity, a potentially lethal side-effect, before drug approval.

Use of Blood to Study Cancer Immunotherapy in Humanized Mouse Models

Project location: Toronto

Estimated project start date: 2022-09-01

Estimated number of cord blood units required to complete this research project: 26

Small cell lung cancer (SCLC) is a deadly disease that affects 15% of all lung cancer patients and has a grim 5-year survival rate of ≤ 7%. Immune checkpoint therapy (ICT) is a novel treatment but has modest benefit in SCLC. Humanized mice models(HuMice)are mice that possess a quasi-functional human immune system generated from injected stem cells. Our research goal is to test whether these novel laboratory models can be used to improve ICT in SCLC. Current mouse models used have only one tumour subtype and possess a mouse immune system, thus results are rarely translatable to humans. Successful development of HuMice can provide a platform to not only test ICT in a human immune system, but also the immunology of multiple subtypes of SCLC. The aim of this study is to develop and characterize HuMice models for use in SCLC by understanding their immune-tumour interaction. Additionally, we aim to identify drugs capable of increasing the antitumour effect of ICT using these HuMice to provide a ready-to-use combination in the clinic. The umbilical cord blood acquired from Canadian Blood Services will fuel the development of a more translatable preclinical model that can help bridge bench-to-bedside research.

Stem Cell Therapy for Post-Stroke Neurovascular Regeneration and Recovery

Project location: Ottawa

Estimated project start date: 2022-10-01

Estimated number of cord blood units required to complete this research project: 96

Stroke-related brain injury results in loss of both neural and vascular cells. The extent of regeneration of both neurons and micro-vessels may limit the level of functional recovery after stroke. Therefore, long-term neuroreparative therapies need to repair the two types of cells to restore cerebral blood flow and promote neural regeneration for stroke recovery. Hereby, we propose to develop an optimal stem cell-based therapy by co-transplantation of both neural and blood vessel stem cells in combination with preconditioning strategy and enriched rehabilitation to augment brain repair and enhance functional recovery. We expect that co-transplantation of both human neural and blood vessel stem cells following injury in a rat stroke model will provide sufficient quantities of all major brain cell types to efficiently regenerate neurovascular units in the damaged brain and improve neurobehavioral recovery, leading to better therapeutic outcomes for the treatment of ischemic stroke. To measure outcomes of these combination therapies, we will evaluate brain damage, quantify the number of grafted cells in the damaged brain, assess functional integration of exogenous neurons and blood vessels in the brain, and assess behavioural recovery profiles using a rat stroke model. Optimizing the stem cell-based therapies with enriched rehabilitation provides a clinically relevant treatment model that has potential to enhance functional integration of robust exogenous grafted cells into undamaged brain regions and improve behavioral recovery following stroke. The cord blood obtained from Canadian blood services will be an essential source for us to generate blood vessel stem cells for this research.

Comparing cancer-targeting effectiveness of umbilical cord versus adult donor CAR-NKs

Project location: Ottawa, Ontario

Estimated project start date: 2023-01-09

Estimated number of cord blood units required to complete this research project: 10

Multiple myeloma (MM) is an incurable, progressive malignancy. While chemotherapy can slow down the progression of this disease, relapses are inevitable and patients with relapsed disease have poor outcomes and few treatment options. Novel therapies involving modified immune cells (CAR-Ts) are highly effective, yet extremely expensive and time consuming to manufacture. Research has recently identified another type of immune cell that can be exploited for a cost-effective, readily available immunotherapy (i.e., CAR-NKs), but extensive research must be conducted prior to moving to clinical
trials.

The objective of this study is to determine the ideal source of NK cells to manufacture CAR-NKs: healthy donors, umbilical cord blood, or patient-derived NK cells. This study will compare CAR-NKs from these different sources to see whether there are significant differences in how effective the CAR-NKs are at killing multiple myeloma (cancer) cells.

These findings will help inform further research to help develop a more cost-effective treatment for relapsed MM by characterizing the efficacy of this immunotherapy and laying the groundwork for clinical trials. Thus, the results of this study are well aligned with the interests of the Canadian Blood Services as we are working towards effective treatment of MM.

Developing a humanized mouse model for anti-cancer drug development

Project location: Winnipeg, Manitoba

Estimated project start date: 2022-11-01

Estimated number of cord blood units required to complete this research project: 10

One of the main drawbacks in anti-cancer therapeutic development is that the use of established cell lines grown in a dish in the laboratory is a poor substitute for the complex environment that tumours are usually found within the body. This is why the vast majority of promising new treatments fail in the clinic.

Patient-derived xenografts (PDX), where patient-derived tumour cells are transplanted into immune deficient mice, have proven to be useful avatars to preclinically assess novel anti-cancer therapeutic strategies. While the immune deficient status of these mice makes such xenografts possible, it is not possible to study how the immune system impacts treatment efficacy.

One solution is to first generate mice with human immune systems prior to PDX. This involves first transplanting human umbilical cord blood cells, which contain within it the seeds of a human immune system, into immune deficient animals. Using
humanized mice as recipients for PDX will provide a powerful platform by which promising new anti-cancer treatments can be preclinically assessed more accurately.

3D Bone Marrow Tissue Engineering for HSC Regenerative Medicine

Project location: Toronto, Ontario

Estimated project start date: 2023-05-01

Estimated number of cord blood units required to complete this research project: 20

Experimentation with HSC and progenitors (HSPC) is challenging. When removed from their native bone marrow niche and placed in vitro, HSC and progenitor (HSPC) cells very quickly (24-72h) lose their function. Mounting evidence suggests that the bone marrow extracellular matrix (ECM) is a critical, yet underappreciated, component of the niche that may be instructive to stem cell regulation.

This research aims to develop technology that discovers in vitro niche conditions and applies this knowledge to elucidate niche interactions. In the long term, this research can lead to the development of readily available tissue-matched engineered bone marrow tissue to be used for transplantation. Canadian bone marrow transplant patients stand to benefit the most with shorter waiting times.

Canadian healthcare savings can also be realized by quickly treating patients and removing them from ever-lengthening transplant waiting lists and the associated healthcare costs in managing sick waiting patients. Furthermore, this research can be applied to test new experimental drugs that unintentionally cause myelosuppression toxicity, a potentially lethal side-effect, before drug approval.

Enhancing blood stem cell self-renewal to improve regenerative therapies

Project location: Toronto, Ontario

Estimated project start date: 2023-05-01

Estimated number of cord blood units required to complete this research project: 144 units/year

Hematopoietic stem cells (HSCs) produce all of the different blood cells in the body, while also replicating (or ‘renewing’) themselves to maintain life-long blood production. Because of this, HSCs are essential for transplant therapies that help to re-establish healthy blood production in patients with compromised blood systems or following chemotherapy and radiation
treatment. While powerful, many patients cannot currently benefit from these HSC sources as umbilical cord blood contains limited numbers, and bone marrow transplants do not always lead to proper HSC uptake and blood regeneration. Although therapeutic approaches have advanced, it remains challenging to expand these key cells both inside and outside the body. Thus, further characterization of the mechanisms that control HSC renewal are needed.

We have previously revealed multiple proteins that when modified in cord blood HSCs have shown to increase cell numbers without negative side effects. Building on this, we aim to further study HSC biology and identify additional unique HSC renewal factors which promote cell expansion inside and outside the body. Doing so will allow for the development of improved regenerative treatments and maximize the use of valuable blood stem cell donations from CBS.

Hematopoietic stem cells, cell engineering and transfusion medicine

Project location: Ottawa, Ontario

Estimated project start date: 2020-07-01

Estimated number of cord blood units required to complete this research project: 300

Umbilical cord blood units are a source of hematopoietic stem cells used for patients without a suitable donor. Collection, processing, and storage under freeze are steps involved in stem cell and cord blood banking. Moreover, new cell culture technologies offer new products that may accelerate graft success in patients. The impact of these processes on graft quality and activity need to be investigated to optimize the quality of the cord blood graft distributed by the Canadian Blood Services. Our projects investigate i) the impact of processing on cord blood quality and potency, ii) test new additive solution to improve the recovery of the graft after freeze, iii) develop new expansion strategies and investigate the impact that such expansion has on graft’ quality and, iv) we combine expansion platforms with gene editing technologies to sought new therapeutic avenues for patients suffering from blood- based inherited gene disorders. Improved quality and new products will translate into improved products of patients in need.

A new role for the molecule ADA2 in the development of human immune cells.

Project Location: Vancouver, BC

Estimated project start date: 2023-06-30

Estimated number of cord blood units to complete this research project: 18

Rationale: We study a rare childhood disease, called Deficiency in Adenosine Deaminase 2 (DADA2), that causes a range of health issues, the most serious being the inability to make immune cells that keep us healthy. We know that children with DADA2 have defects in a protein called ADA2 but we don’t know how ADA2 is involved in immune cell development.

Hypothesis: ADA2 is a growth factor that is important for the development of immune cells. This hypothesis is based on the presence of a growth factor in insects that is similar to human ADA2.

Significance: This will be the first study to look at ADA2 in human immune cell development. Because ADA2 does not exist in rodents, our experiments are best performed on human CD34+ hematopoietic stem cells.

Objectives:

i) determine when and how much ADA2 is present during a 10-14 day window of immune cell development and
ii) measure changes in behavior of defective ADA2 and the impact on immune cell development.
Relevance to CBS: Understanding the factors involved in normal immune cell development (objective i) and how ADA2 defects cause abnormalities in this process (objective ii) is key to the improved understanding and treatment of blood disorders.

Blood stem cells, genetic engineering, transplantation and transfusion

Project Location: Ottawa, ON

Estimated Project Start Date: 2023-10-01

Estimated Number of Cord Units to Complete this research project: 300

Blood stem cells, genetic engineering, transplantation and transfusion

Umbilical cord blood units are a great source of hematopoietic stem cells, and immune cells used for patients without a suitable donor. One of the primary limitations of cord blood units is that there are often not enough cells in one cord unit to support bone marrow transplants in adults. Excitingly, new cell culture technologies offer novel products that help accelerate graft success in patients. The impact of these processes on graft quality and activity need to be investigated to optimize the quality of the cord blood graft distributed by the Canadian Blood Services. Our projects investigate i) develop new expansion strategies and investigate the impact that such expansion has on graft’ quality, and ii) use genome engineering technologies create new stem cell and immune cell products for patients suffering from blood-based inherited gene disorders and cancer.

Developing safe, effective and affordable cell therapies with cord blood

Estimated Project Start Date: 2024-02-01

Estimated number of cord blood units to complete this research project: 18

Summary: Umbilical cord blood has the potential to treat a wide range of diseases such as cancer, immune disorders and genetic disease. Cord blood contains blood stem cells that are capable of renewing themselves and also differentiating into red blood cells that carry oxygen, platelets that enable clotting and immune cells that protect us from infection and cancer. Not only is cord blood itself a useful therapeutic agent, but it can also serve as a cell source for manufacturing immune cells such as T cells that can be used as therapeutics. The purpose of this research is to use cord blood as cell source for producing large quantities of T cells in the dish. We will then test the ability of these cord blood-derived T cells to kill cancer cells in the petri dish. We will also test different methods of genetically modifying the cord blood cells or the resulting T cells to enhance their ability to safely and effectively kill cancer cells.