T cell suicide gene therapy to aid haematopoietic stem cell transplantation

Graft versus host disease (GVHD) is a T cell mediated phenomenon that arises following allogeneic haematopoietic stem cell transplantation, and may be particularly severe in the context of human leukocyte antigen (HLA) mismatched procedures. Although GVHD can be largely abrogated through T cell depletion, such measures result in loss of graft potency and reduced anti-viral and anti-leukaemic effects. The genetic modification of T cells to carry a suicide gene mechanism has been advocated as means of allowing T cells to be harnessed for their beneficial effects, and safely eliminated in the event of significant GVHD. The feasibility of the strategy has been demonstrated in clinical studies using T cells modified by retroviral transduction to encode the herpes simplex thymidine kinase (HSVTK) gene to treat patients with haematological malignancies. However, a number of limitations associated with current protocols have become apparent. Most notably, the process of retroviral transduction, which requires pre-activation of T cells, appears to impair subsequent functional potential. Efforts are now directed towards circumventing the pre-activation requirements of retroviral vectors by using alternative lentiviral systems, in association with improved suicide gene/prodrug combinations.