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. ORCID: https://orcid.org/0000-0001-9416-2737, 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:	05 May 2023 10:27
URI:	https://orca.cardiff.ac.uk/id/eprint/125962

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