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Framework engineering to produce dominant T cell receptors with enhanced antigen-specific function

Thomas, S; Mohammed, F; Reijmers, RM; Woolston, A; Stauss, T; Kennedy, A; Stirling, D; ... Stauss, HJ; + view all (2019) Framework engineering to produce dominant T cell receptors with enhanced antigen-specific function. Nature Communications , 10 (1) , Article 4451. 10.1038/s41467-019-12441-w. Green open access

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Abstract

TCR-gene-transfer is an efficient strategy to produce therapeutic T cells of defined antigen specificity. However, there are substantial variations in the cell surface expression levels of human TCRs, which can impair the function of engineered T cells. Here we demonstrate that substitutions of 3 amino acid residues in the framework of the TCR variable domains consistently increase the expression of human TCRs on the surface of engineered T cells.The modified TCRs mediate enhanced T cell proliferation, cytokine production and cytotoxicity, while reducing the peptide concentration required for triggering effector function up to 3000-fold. Adoptive transfer experiments in mice show that modified TCRs control tumor growth more efficiently than wild-type TCRs. Our data indicate that simple variable domain modifications at a distance from the antigen-binding loops lead to increased TCR expression and improved effector function. This finding provides a generic platform to optimize the efficacy of TCR gene therapy in humans.

Type: Article
Title: Framework engineering to produce dominant T cell receptors with enhanced antigen-specific function
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1038/s41467-019-12441-w
Publisher version: http://dx.doi.org/10.1038/s41467-019-12441-w
Language: English
Additional information: © The Author(s) 2019. This article is licensed under a Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/).
Keywords: Cancer immunotherapy, Protein design, T-cell receptor, Translational immunology
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Infection and Immunity
UCL > Provost and Vice Provost Offices > UCL BEAMS
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Engineering Science
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Engineering Science > Dept of Computer Science
URI: https://discovery.ucl.ac.uk/id/eprint/10083089
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