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

Sharyn Thomas, Fiyaz Mohammed, Rogier M. Reijmers, Annemarie Woolston, Theresa Stauss, Alan Kennedy, David Stirling, Angelika Holler, Louisa Green, David Jones, Katherine K. Matthews, David A. Price, Benjamin M. Chain, Mirjam H. M. Heemskerk, Emma C. Morris, Benjamin E. Willcox and Hans J. Stauss ()
Additional contact information
Sharyn Thomas: Royal Free Hospital
Fiyaz Mohammed: University of Birmingham, Edgbaston
Rogier M. Reijmers: Leiden University Medical Center
Annemarie Woolston: Royal Free Hospital
Theresa Stauss: Royal Free Hospital
Alan Kennedy: Royal Free Hospital
David Stirling: Royal Free Hospital
Angelika Holler: Royal Free Hospital
Louisa Green: Royal Free Hospital
David Jones: University College London
Katherine K. Matthews: Cardiff University School of Medicine
David A. Price: Cardiff University School of Medicine
Benjamin M. Chain: Royal Free Hospital
Mirjam H. M. Heemskerk: Leiden University Medical Center
Emma C. Morris: Royal Free Hospital
Benjamin E. Willcox: University of Birmingham, Edgbaston
Hans J. Stauss: Royal Free Hospital

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-12441-w

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