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Safe and effective immunotherapy of leukaemia with suicide gene-modified human T lymphocytes retaining anti-minor histocompatibility antigen reactivity

Objective

Allogeneic haematopoietic stem cell transplantation (allo-SCT) is the curative option for leukaemia and other haematological tumours. In allo-SCT donor T lymphocytes play a crucial therapeutic role both in providing immunological reconstitution and eradica ting malignant cells. Despite this, the use of donor T cells is limited by the occurrence of fatal graft-versus-host disease (GvHD). A suicide gene codes for a protein able to convert a non-toxic pro-drug into a toxic product. Donor T lymphocytes expressin g the herpes simplex virus-thymidine kinase suicide gene (TK) become sensitive to ganciclovir (GCV) and can be eliminated in the case of GvHD. The aim of this project is to generate TK+ human T lymphocytes that possess substantial anti-leukaemia activity i n vivo. To this I will focus on the response against the HA-1 minor histocompatibility antigen. HA-1 is one of the major targets of immune elimination of leukaemia following allo-SCT, also known as the graft-versus-leukaemia effect (GvL). I will verify in vitro what protocol results in TK+ human T lymphocytes with anti-HA-1 reactivity and test them in vivo for GvL and for GvHD. To this I will treat NOD/scid mice harbouring HA-1+ human leukemias and/or grafted with HA-1+ full-thickness human skin grafts with HA-1-specific TK+ lymphocytes. I will also demonstrate the safety of the treatment, as the possibility to eliminate TK+ cells by GCV administration in vivo. The results of this project will be of paramount importance in the validation of suicide gene ther apy (SGT) as a tool to exploit safe and effective allo-SCT for the cure of haematological and possibly solid tumours.

Call for proposal

FP6-2004-MOBILITY-5
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Funding Scheme

EIF - Marie Curie actions-Intra-European Fellowships

Coordinator

LEIDEN UNIVERSITY MEIDCAL CENTER
Address
Albinusdreef 2, 2333 Za
Leiden
Netherlands