Many of the most promising tumor antigens for T cell-based cancer immunotherapies are unmodified self-antigens. Unfortunately, the avidity of T cells specific for these antigens is limited by central tolerance during T cell development in the thymus, resulting in decreased anti-tumor efficacy of these T cells. One approach to overcome this obstacle is to mutate TCR genes from naturally occurring T cells in order to enhance the affinity for the target antigen. These enhanced affinity TCRs can then be developed for use in TCR gene therapy. Although significantly enhanced affinity TCRs have been generated using this approach, it is not clear if these TCRs, which bypass the affinity limits imposed by negative selection, remain unresponsive to the low levels of self-antigen generally expressed by some normal tissues. Here we show that two variants of a high affinity WT1-specific TCR with enhanced affinity for WT1 are safe, and do not mediate autoimmune tissue infiltration or damage when transduced into peripheral CD8 T cells and transferred in vivo. However, if expressed in developing T cells and subjected to thymic selection, the same enhanced-affinity TCRs signal tolerance mechanisms in the thymus resulting in T cells with attenuated antigen sensitivity in the periphery.
"For example, Wilms tumour antigen 1 (WT1) is expressed in leukaemic cells including acute myeloid leukaemia (AML) and myelodysplastic syndromes (MDS), at much higher levels than in normal stem cells or other tissues. Clinical trials of TCRs directed against HLA-A2/WT1 are being planned to treat relapse of AML/MDS in centres in Japan (Ochi et al, 2011), the USA (Schmitt et al, 2013) and the UK (Xue et al, 2005) The approach is supported by data from a recent experience with (non-engineered) donor-derived WT1-specific CD8 T cells infusions in post-transplant patients where antileukaemic effects were detected without notable toxicities (Chapuis et al, 2013). A similar approach is being used to transduce donorderived T cells from CMV seronegative stem cell donors with a HLA-A0201-restricted/CMV pp65-specific T cell TCR with a view to treating transplant recipients who reactivate CMV following the procedure. "
[Show abstract][Hide abstract] ABSTRACT: Proof-of-concept studies have demonstrated the therapeutic potential of engineered T cells. Transfer of recombinant antigen-specific T cell receptors (TCR) and chimaeric antigen receptors (CARs) against tumour and viral antigens are under investigation by multiple approaches, including viral- and nonviral-mediated gene transfer into both autologous and allogeneic T cell populations. There have been notable successes recently using viral vector-mediated transfer of CARs specific for B cell antigens, but also reports of anticipated and unanticipated complications in these and other studies. We review progress in this promising area of cellular therapy, and consider developments in antigen receptor therapies including the application of emerging gene-editing technologies.
British Journal of Haematology 06/2014; 166(6). DOI:10.1111/bjh.12981 · 4.71 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In this issue of Blood, Schmitt et al address the biology and safety of T cells engineered to express T-cell receptor (TCR) variants endowed with enhanced affinity for tumor-associated antigens.
[Show abstract][Hide abstract] ABSTRACT: In this issue of Blood, Linette et al report a cautionary tale—a lethal off-target toxicity following T-cell receptor (TCR) optimization to enhance affinity against a tumor-associated antigen, MAGE-A3.
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