Enhanced-affinity murine TCRs for tumor/self-antigens can be safe in gene therapy despite surpassing the threshold for thymic selection.

and Department of Immunology and Medicine, University of Washington, Seattle, WA, United States
Blood (Impact Factor: 10.45). 05/2013; 122(3). DOI: 10.1182/blood-2013-01-478164
Source: PubMed


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.

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    • "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. "
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