“Suicide” gene for the control of graft-versus-host disease

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Abstract

Specific and conditional in vivo ablation of alloreactive donor T cells after allogeneic hematopoietic stem cell transplantation could significantly contribute to preventing and treating graftversus-host disease (GVHD). The use of donor T cells expressing a “suicide” gene such as the thymidine kinase gene of the herpes simplex virus 1 (HS-tk) has the potential of achieving such a goal. Ex vivo retroviral-mediated HS-tk gene transfer in human T cells as well as ganciclovir sensitivity of such gene-modified T cells is established. The prevention and treatment of GVHD induced by HS-tk-expressing donor T cells by ganciclovir has been demonstrated in murine models. Clinical trials involving the use of HS-tk-expressing T cells at time of transplantation in conjunction with a T-cell-depleted hematopoietic graft or subsequently for treatment of relapse or lymphoma associated with Epstein-Barr virus infection are currently underway. In vivo circulation of ganciclovir-sensitive gene-modified cells as well as the occurrence of ganciclovir-sensitive acute and chronic GVHD have been documented. If these initial exciting findings are confirmed, such an approach could significantly contribute to expanding the use of alloreactivity as a treatment modality.

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