WP04 - Clinical trial for the treatment of acute steroid refractory GVHD after allogeneic HSCT

Objectives of the workpackage

The objective in work package 4 is to prepare and conduct a clinical trial that determines the safety and efficacy of adoptively transferring regulatory T cells to patients after bone marrow transplantation that suffer from Graft-versus-Host Disease.

Workpackage description

Graft-versus-Host Disease (GvHD) is a major complication following allogeneic hematopoietic stem cell transplantation (HSCT), and is associated with significant morbidity and mortality.

The current paradigm is that GvHD is caused by donor-derived T lymphocytes specific for broadly expressed minor histocompatibility antigens, and there is more emerging evidence that additional lymphocyte subsets and also innate immune cells play a role in initiating and sustaining GvHD. The current standard of care for GvHD is the use of immunosuppressive agents including steroids - however, there is a substantial fraction of patients in which these strategies are insufficient and/or unable to control GvHD and thus, novel innovative approaches for the treatment of GvHD are urgently needed.

It has been shown in pre-clinical models in vitro and in vivo that the subset of regulatory T cells (T regs) - that have immunomodulatory/-suppressive properties - has the ability to mitigate the severity and extent of GvHD, and there is preliminary evidence from pilot clinical trials that the adoptive transfer of T regs to patients suffering from GvHD after allogeneic HSCT is feasible and safe.   

In this work package, the investigators will analyse in a clinical trial, whether the infusion of regulatory T cells to patients suffering from therapy-refractory GvHD following allogeneic HSCT is able to reduce GvHD severity and is associated with a clinical benefit.

In preliminary work the investigators have developed methodologies for the isolation of T regs from umbilical cord blood as an alternative source using novel, highly sensitive cell selection strategies. The investigators will continue to refine this approach with the aim of developing a protocol for the generation of 'third-party' T regs that are available 'off the shelf' and can be administered to any patient with GvHD in need of therapy (WP2).

The investigators have planned to perform a non-randomized, phase I/II trial of using umbilical cord blood regulatory T cells to treat acute GvHD as a multicenter trial at the three participating institutions. As part of this work package, the investigators will develop and compile all necessary documentation for the clinical trial, seek regulatory and ethics approval, and once approval has been obtained, treat and monitor eligible patients with GvHD.