Generation of suppressive donor T cells to specifically control alloresponses after allogeneic stem cell transplantation

Lead Research Organisation: Queen Mary, University of London
Department Name: Barts Cancer Institute

Abstract

Allogeneic stem cell transplantation consists of the transfer of blood stem cells (or bone marrow) from a healthy donor to a patient. This procedure can cure patients with many diseases that would be otherwise incurable, including those with cancers of the blood such as leukaemia. However, a major problem that limits the success of allogeneic stem cell transplantation is graft-versus-host disease, which is the destruction of healthy patient tissues by donor immune cells contained within the transplant. Current techniques to prevent graft-versus-host disease are unsatisfactory as they suppress the recovery of all immune cells, resulting in increased infection and cancer relapse after transplant. We have recently identified a way of manipulating human donor cells before allogeneic transplantation that leads to the production of immune cells which can suppress graft-versus-host disease responses. The aim of this project is to develop ways in the laboratory to improve this technique to provide donor immune cells which could be used to prevent graft-versus-host disease without affecting the healthy recovery of the immune system after allogeneic transplantation. We hope that this might lead to a better way to prevent graft-versus-host disease after allogeneic transplantation, making this a safer and more effective treatment.

Technical Summary

Allogeneic haematopoietic stem cell transplantation (AHSCT) can cure patients with many diseases for which no effective alternative therapy exists. A major challenge to AHSCT is graft-versus-host disease (GvHD), mediated by alloreactive donor T cells which recognize and damage healthy patient tissues. Current methods to prevent GvHD are unsatisfactory, delaying reconstitution of beneficial donor T cells and increasing infection and disease relapse. The development of strategies to selectively reduce alloreactive T cell responses could improve the outcome of AHSCT. One such strategy is alloanergization, the inactivation of alloreactive donor T cells by allostimulation with co-stimulatory blockade. Alloanergization preserves pathogen-specific T cell responses. In early clinical studies, transplantation of alloanergized HLA-mismatched donor T cells within bone marrow resulted in rapid immune reconstitution, few infections and low rates of GvHD. We have recently shown that the strategy of alloanergization results in the generation of regulatory T cells (Treg) which specifically suppress alloreactive donor T cell responses. We therefore hypothesise that alloanergized donor cells could be used for specific prophylaxis of GvHD after AHSCT. The development of alloanergization as a strategy to generate Treg which prevent GvHD without impairing graft-versus-leukaemia (GvL) effects after AHSCT is the objective of this project. The first aim is to potentiate the generation of allospecific Treg following alloanergization. We will use in vitro assays to determine the effects of epigenetic modulation of FOXP3 expression on the frequency, suppressive function and migratory capacity of Treg generated by alloanergization of human peripheral blood mononuclear cells (PBMC). To broaden the applicability of the approach, we will also modify the strategy for use with HLA-matched unrelated donors using established approaches to augment antigen-presentation. The second aim is to determine if alloanergized cells can prevent human T cells from causing GvHD in vivo. This will be achieved using adoptive transfer of human PBMC with and without alloanergized cells into immunodeficient NOD/SCID/IL2R-/- mice in a xenogeneic model of human T cell-mediated GvHD. Finally, a critical component for successful use of alloanergized human cells to prevent GvHD after AHSCT is the preservation of GvL effects. Our third aim is to enhance donor cell-mediated GvL effects after alloanergization by employing non-haematopoietic antigen-presenting cells to spare tissue-restricted minor histocompatibility antigen-directed T cell responses, and to augment alloreactive donor NK cell responses after alloanergization. This project could lead to development of effective clinical strategies to deliver antigen-specific cellular prophylaxis of GvHD which could improve the outcome of ASCT.

Publications

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Barbon CM (2014) Alloanergization of human T cells results in expansion of alloantigen-specific CD8(+) CD28(-) suppressor cells. in American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons

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Davies JK (2018) Infusion of Alloanergized Donor Lymphocytes after CD34-selected Haploidentical Myeloablative Hematopoietic Stem Cell Transplantation. in Clinical cancer research : an official journal of the American Association for Cancer Research

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Davies JK (2012) Blockade of chemotaxis in graft-versus-host disease. in The New England journal of medicine

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Kotsiou E (2016) Allospecific Tregs Expanded After Anergization Remain Suppressive in Inflammatory Conditions but Lack Expression of Gut-homing Molecules. in Molecular therapy : the journal of the American Society of Gene Therapy

 
Description Project grants
Amount £185,000 (GBP)
Organisation Bloodwise 
Sector Charity/Non Profit
Country United Kingdom
Start 08/2015 
End 07/2018
 
Description clinical research fellowship
Amount £130,000 (GBP)
Organisation Barts Charity 
Sector Charity/Non Profit
Country United Kingdom
Start 05/2016 
End 04/2018
 
Description small project grant
Amount £6,100 (GBP)
Organisation Barts Charity 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2015 
End 03/2016
 
Description Expanding peripheral blood derived endothelial cells for use as tolerizing antigen-presenting cells 
Organisation Imperial College London
Department National Heart & Lung Institute (NHLI)
Country United Kingdom 
Sector Academic/University 
PI Contribution developing assays to assess antigen-presenting cell capacity
Collaborator Contribution helped my group with ex vivo cell culture approaches
Impact None
Start Year 2011
 
Description Using humanized anti-B7 antibodies for costimulatory blockade to separate allospecific effector T cell and regulatory T cell responses 
Organisation Dana-Farber Cancer Institute
Department Department of Medical Oncology
Country United States 
Sector Academic/University 
PI Contribution collaborative experimental desigh and execution
Collaborator Contribution source of reagents
Impact None
Start Year 2011
 
Description School visis st Albans 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Workshop Facilitator
Geographic Reach Local
Primary Audience Schools
Results and Impact pupils attanded a working in science workshop

school reported interest from several individuals after workshop
Year(s) Of Engagement Activity 2012