Immunotherapy research group

Using a targeted profiling technique we are aiming to classify hundreds of donor samples based on the genes their white blood cells express. This will allow us to identify a panel of biomarkers that are linked to more favourable transplant outcomes. It could then be possible to use these markers as indicators to predict which donors will be more suitable for future transplants.

This project is a collaborative effort with Professor Sergio Rutella at Nottingham Trent University (NTU).

We have shown that if there is a higher proportion of regulatory T-cells (Tregs) compared to total T-cells in the graft from an adult donor, it improves the chance of a successful transplant.

We want to extend this study to patients who received an umbilical cord blood transplant.

Our aim is to measure the Treg/T-cell ratios on cord blood samples used in historical transplants using a novel DNA based technique and determine if this had an impact on the success of the transplants they were used in. We are analysing approximately 400 DNA samples which our collaborators at the Banc di Sang et Texis in Barcelona have collected, and for who we have clinical data obtained by our partners at Eurocord.

Key publications 

Enumerating regulatory T cells in cryopreserved umbilical cord blood samples using FOXP3 methylation specific quantitative PCR. 
Duggleby, R. C., Tsang, H. P., Strange, K., McWhinnie, A., Lamikanra, A. A., Roberts, D. J., Hernandez, D., Madrigal, J. A., & Danby, R. D. 
PLoS One (2020) 15, e0240190 

High proportions of regulatory T cells in PBSC grafts predict improved survival after allogeneic haematopoietic SCT 
Danby, R. D., Zhang, W., Medd, P., Littlewood, T. J., Peniket, A., Rocha, V., & Roberts, D. J. 
Bone Marrow Transplantation (2016) 51(1), 110–118. 

Natural Killer (NK) cells are in important part of our immune system that can target and destroy blood cancer cells. They express a gene called NKG2D, which helps them perform this role, but unfortunately when this gene gets turned off, it can increase the chance of relapse after transplant. The NKG2D signal is regulated in many ways including microRNAs binding.

Variations in a single DNA base in the NKG2D gene stops the mircoRNA-1245 binding so it can’t alter the gene’s expression and affect NK cell function. Variations like this occur naturally in the population and are called single nucleotide polymorphisms (SNPs). We now want to know if donor cells that have this SNP, along with another in a different gene, influence the success of cord blood transplants.

Alongside this work we are exploring the use of CRISPR/Cas9 to modify the regulation of NK cell receptor genes to create new modified NK cell lines that are more efficient at targeting and removing cancer cells.

Key publications 

Functional Characterisation and Analysis of the Soluble NKG2D Ligand Repertoire Detected in Umbilical Cord Blood Plasma. 
Cox, S. T., Danby, R., Hernandez, D., Laza-Briviesca, R., Pearson, H., Madrigal, J. A., & Saudemont, A. 
Frontiers In Immunology (2018), 9, 1-17

Using donated live immune cells to target and remove cancer cells is a promising treatment option for blood cancers. NK (natural killer) cells, a type of white blood cell that targets abnormal cells like cancer cells could be an ideal candidate for this type of cell therapy. This is because they can be isolated readily from third party sources as they do not need to be HLA matched with the patient. They have the potential to eliminate residual malignant cells and prevent relapse.

We believe that using a combination of techniques, NK cells from umbilical cord blood can be rapidly expanded on a large scale and used as an ‘off-the-shelf’ cancer immunotherapy for a much wider range of patients.

We are collaborating with a number of researchers to combine the expansion platform with the genetic modification of NK cells to make more potent cell therapies.

Key publications 

Umbilical Cord Blood Natural Killer Cells, Their Characteristics, and Potential Clinical Applications. 
Sarvaria, A., Jawdat, D., Madrigal, J. A., & Saudemont, A. 
Frontiers In Immunology (2017), 8, 329. 

Cryopreservation has no effect on function of natural killer cells differentiated in vitro from umbilical cord blood CD34(+) cells. 
Domogala, A., Madrigal, J. A., & Saudemont, A. 
Cytotherapy, (2016) 18(6), 754–759. 

Natural Killer Cell Immunotherapy: From Bench to Bedside. 
Domogala, A., Madrigal, J. A., & Saudemont, A. 
Frontiers In Immunology (2015) 6, 264 

Differential activation of cord blood and peripheral blood natural killer cells by cytokines. 
Alnabhan, R., Madrigal, A., & Saudemont, A. 
Cytotherapy (2015), 17(1), 73–85. 

The unique profile of cord blood natural killer cells balances incomplete maturation and effective killing function upon activation. 
Luevano, M., Daryouzeh, M., Alnabhan, R., Querol, S., Khakoo, S., Madrigal, A., &  Saudemont, A. 
Human Immunology (2012), 73(3), 248–257. 

Transcription factors involved in the regulation of natural killer cell development and function: an update. 
Luevano, M., Madrigal, A., & Saudemont, A. 
Frontiers In Immunology (2012) 3, 319. 

MSCs are known to be immunosuppressive and can also promote tissue repair and haematopoiesis. These properties, plus the fact that the immune system does not react to them, make them ideal candidates for cell therapy. They exert theses effects through a wide range of signalling molecules they secrete including IDO, several interleukins, PD-Ls and HLA-G5.

MSC-based therapies in immune diseases have performed inconsistently in clinical trials, potentially due to variation on how they are defined, collected and grown for clinical use. This has highlighted the need for a standardised development protocol that maintains the high immunosuppressive potential of these cells.

Our current project has two main aims:

1. Test and standardise an efficient method of isolating and culturing MSCs from cord tissue, producing cells that meet a set of defined characteristics.
2. Identify and test methods for genetically enhancing the immunosuppressive capacity of MSCs and their ability to combat GvHD after transplant.

Using cord blood to perform a stem cell transplant has many advantages including being more readily available (following banking and testing) and HLA mismatches are better tolerated with lower risks of GvHD. However, the time needed for engraftment after transplant is longer and the total number of cells in a single cord blood unit is often too small to treat an adult. This means technologies which can expand the number of cells in a single unit, while maintaining their ability to reproduce and enhance early engraftment could be of huge clinical benefit and make cord blood more economically viable.

Anthony Nolan is collaborating with the UK based biotechnology company Plasticell Ltd, which has developed and patented a novel method for growing the stem cells found in blood that also ensures they are still suitable for transplant. It delivers a much larger expansion (up to 500-fold) of the stem cell population needed for engraftment in just six days.

In collaboration with the Cell and Gene Therapy Catapult, Plasticell Ltd has developed a suitable manufacturing process and we are now working on additional development work so that this therapy can progress into clinical trials.

This is a collaborative project between Plasticell Ltd, The Francis Crick Institute and Anthony Nolan, with funding from Innovate UK.

Key publications 

Modified CD34+ hematopoietic stem and progenitor cell isolation strategy from cryopreserved human umbilical cord blood.  
Mata, M. F., Hernandez, D., Rologi, E., Grandolfo, D., Hassan, E., Hua, P., Kallmeier, R., Hirani, S., Heuts, F., Tittrea, V., Choo, Y., Baradez, M. O., Watt, S. M., & Tarunina, M.  
Transfusion (2019) 59(12), 3560–3569. 

Hernandez, D. Hematopoietic stem cell expansion. (2018). WO 2018/197868