Enhanced-affinity murine TCRs for tumor/self-antigens can be safe in gene therapy despite surpassing the threshold for thymic selection.
ABSTRACT 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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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
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ABSTRACT: Over the last several years, there has been considerable progress in the treatment of cancer using gene modified adoptive T cell therapies. Two approaches have been used, one involving the introduction of a conventional αβ T cell receptor (TCR) against a pepMHC cancer antigen, and the second involving introduction of a chimeric antigen receptor (CAR) consisting of a single-chain antibody as an Fv fragment linked to transmembrane and signaling domains. In this review, we focus on one aspect of TCR-mediated adoptive T cell therapies, the impact of the affinity of the αβ TCR for the pepMHC cancer antigen on both efficacy and specificity. We discuss the advantages of higher-affinity TCRs in mediating potent activity of CD4 T cells. This is balanced with the potential disadvantage of higher-affinity TCRs in mediating greater self-reactivity against a wider range of structurally similar antigenic peptides, especially in synergy with the CD8 co-receptor. Both TCR affinity and target selection will influence potential safety issues. We suggest pre-clinical strategies that might be used to examine each TCR for possible on-target and off-target side effects due to self-reactivities, and to adjust TCR affinities accordingly.Frontiers in Immunology 01/2013; 4:244. DOI:10.3389/fimmu.2013.00244
- Blood 07/2013; 122(3):304-6. DOI:10.1182/blood-2013-06-504100