%0 Journal Article
%T Improving TCR Gene Therapy for Treatment of Haematological Malignancies
%A Emma Nicholson
%A Sara Ghorashian
%A Hans Stauss
%J Advances in Hematology
%D 2012
%I Hindawi Publishing Corporation
%R 10.1155/2012/404081
%X Adoptive immunotherapy using TCR gene modified T cells may allow separation of beneficial Graft versus tumour responses from harmful GvHD. Improvements to this include methods to generate high avidity or high affinity TCR, improvements in vector design and reduction in mispairing. Following adoptive transfer, TCR transduced T cells must be able to survive and persist in vivo to give most effective antitumour responses. Central memory or naive T cells have both been shown to be more effective than effector cells at expanding and persisting in vivo. Lymphodepletion may enhance persistence of transferred T cell populations. TCR gene transfer can be used to redirect CD4 helper T cells, and these could be used in combination with CD8+ tumour specific T cells to provide help for the antitumour response. Antigen specific T regulatory T cells can also be generated by TCR gene transfer and could be used to suppress unwanted alloresponses. 1. Introduction Allogeneic haematopoietic stem cell transplantation (HSCT) is an effective treatment for many haematological malignancies. In addition, unselected donor lymphocyte infusions (DLIs) can be utilized to successfully treat relapsed leukaemia after HSCT [1]. Depending on the degree of HLA mismatch, donor T cells recognize alloantigens derived from allogeneic MHC or from polymorphic minor histocompatibility antigens (mHags) expressed by the host. Whilst able to deliver beneficial Graft versus Tumour effects (GvT), alloreactive T cells may also direct their response against normal tissues resulting in Graft versus Host Disease (GvHD), and this is one of the leading causes of transplant-related morbidity and mortality. The incidence of GvHD can be reduced by utilizing T-cell-depleted transplants-but this also leads to an increase in disease relapse rate [2¨C4]. How best to deliver effective GvT responses whilst minimizing harmful GvHD remains a significant challenge. Refining the concept of donor lymphocyte infusions by isolating donor lymphocytes that have known tumour reactivity may result in more effective GvT. Falkenburg et al. have utilized donor-derived leukaemia reactive cytotoxic T lymphocytes (CTLs) to treat a patient with relapsed accelerated phase CML after HSCT [5]. The patient, who had previously been resistant to DLI, went on to achieve a complete remission as a result of this therapy. A phase I/II study looking at generating leukaemia reactive CTLs for patients with relapsed leukaemia after HSCT found that whilst this strategy was feasible, it was complex and time consuming requiring improvements before
%U http://www.hindawi.com/journals/ah/2012/404081/