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

  • Nat Commun. 2019 Oct 1;10(1):4451. doi: 10.1038/s41467-019-12441-w.
Sharyn Thomas  1 ,  Fiyaz Mohammed  2 ,  Rogier M Reijmers  3 ,  Annemarie Woolston  1 ,  Theresa Stauss  1 ,  Alan Kennedy  1 ,  David Stirling  1 ,  Angelika Holler  1 ,  Louisa Green  1 ,  David Jones  4 ,  Katherine K Matthews  5 ,  David A Price  5 ,  Benjamin M Chain  1 ,  Mirjam H M Heemskerk  3 ,  Emma C Morris  1 ,  Benjamin E Willcox  2 ,  Hans J Stauss  6
Affiliations
  • 1. Institute of Immunity and Transplantation, Division of Infection and Immunity, University College London, Royal Free Hospital, London, NW3 2PF, UK.
  • 2. Cancer Immunology and Immunotherapy Centre, Institute for Immunology and Immunotherapy, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK.
  • 3. Department of Hematology, Leiden University Medical Center, 2300 RC, Leiden, The Netherlands.
  • 4. Department of Computer Science, University College London, London, WC1E 6BT, UK.
  • 5. Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, CF10 3AT, UK.
  • 6. Institute of Immunity and Transplantation, Division of Infection and Immunity, University College London, Royal Free Hospital, London, NW3 2PF, UK. [email protected].
PMID: 31575864 DOI: 10.1038/s41467-019-12441-w
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.