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

Research output: Contribution to journalArticle

Authors

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

Colleges, School and Institutes

External organisations

  • University College London
  • Leiden University
  • Cardiff University

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.

Details

Original languageEnglish
Article number4451
Number of pages15
JournalNature Communications
Volume10
Issue number1
Publication statusPublished - 1 Oct 2019