Engineering lymphocyte subsets: tools, trials and tribulations

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Abstract
In principle, the goal of lymphocyte engineering is to pharmacologically enhance the function of the immune system, including specifying antigen recognition, improving lymphocyte survival, augmenting proliferative capacity, preventing apoptosis and/or inducing resistance to immune regulation. Improved understanding of lymphocyte subsets has recently allowed adoptive transfer of CD4+ effector T cells, CD4+ regulatory T cells and CD8+ cytotoxic T cells. In addition to the previous clinical trials testing T cells expressing αβ T cell receptors, clinical protocols evaluating infusions of γδ T cells and invariant natural killer T cells have recently been completed. For many years the only established method to engineer lymphocytes for clinical protocols used gammaretroviruses. Technological advances have produced lentiviral vectors and foamy virus vectors that have increased efficiency and potentially enhanced safety features, zinc-finger nucleases that allow site-specific modification and various other non-viral approaches such as transposons. The most important questions currently facing the field are whether engineered lymphocytes are safe and, if so, under what conditions? Malignancies arising from retrovirally transduced haematopoietic stem cells have been reported in animal models and human gene therapy trials. Several hundred patients have been treated with engineered mature T cells for various indications including congenital immunodeficiency, cancer and AIDS following HIV infection. In contrast to stem cell engineering, to date there are no reported cases of transformation or leukaemia following engineered T cell transfer. The first Phase III clinical study with engineered lymphocytes is currently testing whether allogeneic T cells can mediate immune reconstitution and antileukaemic effects and improve safety by triggering a conditional suicide gene comprised of herpes simplex virus thymidine kinase in the event of graft-versus-host disease.