Framework engineering to produce dominant T cell receptors with enhanced antigen-specific function
Research output: Contribution to journal › Article › peer-review
Authors
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 language | English |
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Article number | 4451 |
Number of pages | 15 |
Journal | Nature Communications |
Volume | 10 |
Issue number | 1 |
Publication status | Published - 1 Oct 2019 |