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

Thomas, Sharyn, Mohammed, Fiyaz, Reijmers, Rogier M., Woolston, Annemarie, Stauss, Theresa, Kennedy, Alan, Stirling, David, Holler, Angelika, Green, Louisa, Jones, David, Matthews, Katherine K., Price, David A., Chain, Benjamin M., Heemskerk, Mirjam H. M., Morris, Emma C., Willcox, Benjamin E. and Stauss, Hans J. 2019. Framework engineering to produce dominant T cell receptors with enhanced antigen-specific function. Nature Communications 10 , -. 10.1038/s41467-019-12441-w

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Publisher: Nature Research
ISSN: 2041-1723
Date of First Compliant Deposit: 10 October 2019
Date of Acceptance: 26 August 2019
Last Modified: 11 Oct 2019 10:15
URI: http://orca-mwe.cf.ac.uk/id/eprint/125962

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