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

Sharyn Thomas; Fiyaz Mohammed; Rogier Reijmers; Annemarie Woolston; Theresa Stauss; Alan Kennedy; David Stirling; Angelika Holler; Louisa  Green; David Jones; Kathaerine K Matthews; David A Price; Benjamin  Chain; Mirjam HM Heemskerk; Emma Morris; Benjamin Willcox; Hans J Stauss

doi:10.1038/s41467-019-12441-w

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

Sharyn Thomas, Fiyaz Mohammed, Rogier Reijmers, Annemarie Woolston, Theresa Stauss, Alan Kennedy, David Stirling, Angelika Holler, Louisa Green, David Jones, Kathaerine K Matthews, David A Price, Benjamin Chain, Mirjam HM Heemskerk, Emma Morris, Benjamin Willcox, Hans J Stauss

Immunology and Immunotherapy

Research output: Contribution to journal › Article › peer-review

9 Citations (Scopus)

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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.

Original language	English
Article number	4451
Number of pages	15
Journal	Nature Communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-12441-w
Publication status	Published - 1 Oct 2019

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

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Thomas_et_al_Framework_engineering_to_produce_dominant_T_cell_receptors_Nature_Communications_2019
Checked for eligibility: 09/10/2019
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Thomas, S., Mohammed, F., Reijmers, R., Woolston, A., Stauss, T., Kennedy, A., Stirling, D., Holler, A., Green, L., Jones, D., Matthews, K. K., Price, D. A., Chain, B., Heemskerk, M. HM., Morris, E., Willcox, B., & Stauss, H. J. (2019). Framework engineering to produce dominant T cell receptors with enhanced antigen-specific function. Nature Communications, 10(1), Article 4451. https://doi.org/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.",

author = "Sharyn Thomas and Fiyaz Mohammed and Rogier Reijmers and Annemarie Woolston and Theresa Stauss and Alan Kennedy and David Stirling and Angelika Holler and Louisa Green and David Jones and Matthews, {Kathaerine K} and Price, {David A} and Benjamin Chain and Heemskerk, {Mirjam HM} and Emma Morris and Benjamin Willcox and Stauss, {Hans J}",

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Thomas, S, Mohammed, F, Reijmers, R, Woolston, A, Stauss, T, Kennedy, A, Stirling, D, Holler, A, Green, L, Jones, D, Matthews, KK, Price, DA, Chain, B, Heemskerk, MHM, Morris, E, Willcox, B & Stauss, HJ 2019, 'Framework engineering to produce dominant T cell receptors with enhanced antigen-specific function', Nature Communications, vol. 10, no. 1, 4451. https://doi.org/10.1038/s41467-019-12441-w

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AU - Thomas, Sharyn

AU - Mohammed, Fiyaz

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AU - Stauss, Theresa

AU - Kennedy, Alan

AU - Stirling, David

AU - Holler, Angelika

AU - Green, Louisa

AU - Jones, David

AU - Matthews, Kathaerine K

AU - Price, David A

AU - Chain, Benjamin

AU - Heemskerk, Mirjam HM

AU - Morris, Emma

AU - Willcox, Benjamin

AU - Stauss, Hans J

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AB - 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.

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

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