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UK funding (£232,495): Modulating human alloresponses with lenalidomide to improve the outcome of allogeneic haematopoietic stem cell transplantation Ukri1 Oct 2014 UK Research and Innovation, United Kingdom
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Modulating human alloresponses with lenalidomide to improve the outcome of allogeneic haematopoietic stem cell transplantation
| Abstract | Each year thousands of people undergo allogeneic stem cell transplantation (AHSCT) to try to cure them of blood cancers. For many it is the only chance of cure, as treatment with chemotherapy has been ineffective. AHSCT involves transplanting healthy bone marrow-derived stem cells from a donor into a patient. It was initially thought that this approach cured cancer by allowing higher doses of toxic chemotherapy and radiotherapy to be given which killed cancer cells more effectively. However, it is now known that AHSCT cures cancer by a process called alloreactivity. This occurs when donor immune cells present within the stem cell transplant recognise patient cells as foreign and damage or kill them. These donor immune cells are called alloreactive cells. The most important alloreactive immune cells are T cells. When donor alloreactive T cells target cancerous patient tissue this results in the benefical graft-versus-tumour (GvT) effect which prevents the cancer coming back. Unfortunately, as well as killing tumour cells, alloreactive donor T cells can also recognise and damage healthy patient tissues which results in harmful graft-versus-host disease (GvHD). It is unlikely that GvT effects and GvHD can be completely separated as they are closely interelated. However, many doctors are trying to develop ways to strengthen GvT effects without increasing GvHD, to improve the outcome of patients undergoing AHSCT. For this reason it is important to look at ways of enhancing alloreactivity that can selectively promote GvT effects. One way to do this may be to use drugs that promote activation of donor alloreactive immune cells and develop new ways to use such drugs after allogeneic stem cell transplantation. Lenalidomide is a new drug that has been shown in the laboratory to increase activation of T cells when they are artifically stimulated. In addition, lenalidomide can improve recognition of tumour cells by the patients own immune cells. Thus this drug has great potential for use to increase GvT effects by stimulating alloreactivity after allogeneic stem cell transplantation. However, early clinical experience giving lenalidomide maintenence therapy to patients after AHSCT has resulted in an increase in GvHD which limits the current approach. Very little is known about how lenalidomide affects human immune alloreactivity and a better understanding of this will help us used more safely and effectively to improve GvT effects after AHSCT. We have already shown for the first time in our laboratory that lenalidomide exposure increases human alloreactivity by selectively increasing growth of a subset of donor T cells called CD8+ cells, and that these cells have a unique pattern of the genes they express. Thus we have already identified the donor alloreactive cell subset potentiated by lenalidomide and several cellular pathways likely to mediate this effect. This project now seeks to build on these important findings with a series of laboratory experiments aimed at identifying the best way to use lenalidomide to maximize beneficial GvT without causing too much harmful GvHD. We will use cells from volunteer donors to further characterize the alloreactive CD8+ cells in both tissue-mismatched and -matched settings. We will use models to represent different ways lenalidomide could be given to pateints (e.g before, during or after the transplant) and use donor immune cells from different sources that are used clinically in AHSCT e.g adult or umbilical cord blood cells. Finally we will measure the effect of lenalidomide on several immune pathways that can selectively potentiate GvT but not GvHD. These studies will define the optimal way to use lenalidomide to potentiate alloreactive responses to strengthen GvT without excessive GvHD after AHSCT. Once defined, thes strategies could be directly translated to early phase clinical trials to try and improve the outcome of AHSCT for pateints with blood cancers. |
| Category | Fellowship |
| Reference | MR/M001733/1 |
| Status | Closed |
| Funded period start | 01/10/2014 |
| Funded period end | 30/09/2017 |
| Funded value | £232,495.00 |
| Source | https://gtr.ukri.org/projects?ref=MR%2FM001733%2F1 |
Participating Organisations
| Queen Mary University of London |
The filing refers to a past date, and does not necessarily reflect the current state. The current state is available on the following page: Queen Mary University of London, London.
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