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Our research across four complementary themes brought the expertise of a variety of leading scientific researchers and academic clinicians, and nurtured an effective transfer of skills with NHSBT.
Haematopoietic stem cell transplants are often the only way to treat inherited genetic disorders or cancers of blood and lymph nodes, but carry significant risks. Following transplants, patients can suffer relapse, infections or graft-versus-host disease, where immune cells in the donor blood attack the patient's body.
The BTRU in Stem Cells and Immunotherapies aimed to minimise these risks by developing techniques to identify more appropriate blood donors, remove the immune cells that attack patients but not those that fight infection, and genetically modify immune cells to target cancer cells. We developed ways to use patients' own cells in treatments, avoiding the need for transplantation altogether and potentially offering new treatments for a wide range of cancers.
Our research was organised across four complementary research themes. Each brought the expertise of a variety of leading scientific researchers and academic clinicians, and facilitating efficient transfer of skills between then and NHSBT.
Theme 1: Improving donor selection or cellular composition of stem cell graft for transplantation
Lead: Professor Stephan Beck
Epigenetic profiling
Graft-versus-host disease (GvHD) and infection remain significant obstacles to improving transplant outcomes. The ability to predict with better accuracy the likelihood of GvHD with any particular donor-recipient pairing is well established to improve post-transplant outcomes. While predictive tools based on genetic profiling and HLA-typing are generally the focus of attention, epigenetic profiling of either the donor, the recipient, or of differences between them remain relatively unexplored. Therefore, we investigated epigenetic signatures that could have been used to better match donors to recipients and help limit the incidence of GvHD without compromising the immune system.
Theme 2: Therapeutic gene modification in malignant disorders or inherited genetic disorders
Lead: Professor Amit Nathwani
Gene Therapy
Senior researchers within the BTRU in Stem Cells and Immunotherapies have extensive experience relating to genetic modification of both stem cells and of T-cells in order to correct genetic defects or enhance anti-tumour activity respectively. We used this knowledge and experience to refine strategies to treat inherited genetic disorders by investigating improved vector design and evaluating alternative gene editing technologies - examining their potential to influence the activity of target genes, and, modify T-cell behaviour. Further work focused on advances in chimeric antigen receptor (CAR) T-cell therapies and crossed over with Theme 3.
Theme 3: Cellular therapies to prevent or treat post-transplant relapse
Lead: Dr Claire Roddie
T-cell therapies
Researchers applied their in-depth knowledge and experience of the use of unmanipulated donor lymphocyte infusions (DLIs) both to prevent and treat relapse following stem cell transplants. Whilst the anti-tumour activity of DLIs is well established, Graft-versus-Host Disease (GvHD) is the major toxic side effect that can be fatal. Separation of GvHD from Graft-versus-Tumour Activity is difficult as they largely depend on the same T-cell receptor (TCR)-mediated recognition of different tissue-specific antigens.
The researchers significantly advanced CAR T-cell therapy treatments for patients with blood cancers, when their cancer comes back (relapse) after a stem cell transplant or does not respond to available treatments (refractory). They raised understanding about this new treatment in the BBC Two documentary 'War in the Blood' and secured additional funds for progressing CAR T-cell therapies for blood and other cancers and clinical delivery of these therapies in the NHS and research including the Sir Naim Dangoor Centre for Cellular Immunotherapy at University College London Hospitals. Find out more about UCL CAR T programme.
Plain English summary of ALLCAR19 results, a CAR T-cell therapy clinical study for adults with relapsed/refractory B-cell Acute Lymphoblastic Leukeamia- Publication: Roddie C, Dias J, O'Reilly MA, Abbasian M, et al. Durable Responses and Low Toxicity After Fast Off-Rate CD19 Chimeric Antigen Receptor-T Therapy in Adults With Relapsed or Refractory B-Cell Acute Lymphoblastic Leukemia. J Clin Oncol. 2021 Oct 20;39(30): 3352-3363.
Theme 4: Manufacturing technology for genetic modification of stem cells or T-cells for therapy
Lead: Professor Adrian Thrasher
Manufacturing cells for therapeutic application
We developed automation and standardisation of the complex stem- and T-cell processing procedures to aid initial process development and eventual scale out of manufacturing. This aim aligned with the strengths and strategic imperatives of NHSBT to be a major partner in the future development of early phase studies in the area, as well as providing the skills and resources for later phase investigations, and ultimately routine delivery of therapies that become the standard of care.
1 December 2020 - T cell immunotherapies have to be made with the patient’s own white blood cells to prevent the treatment from turning on the body of the patient and causing graft versus host disease (donated cells attacking the recipient’s body). The need to produce these therapies for each individual patient limits the wide-spread availability of this therapy as 1) it requires a centre with the expertise to make them and 2) the relatively long time to produce the therapy (~2 weeks) is not be suitable for all patients.
