TY - JOUR
T1 - Framework engineering to produce dominant T cell receptors with enhanced antigen-specific function
AU - Thomas, Sharyn
AU - Mohammed, Fiyaz
AU - Reijmers, Rogier
AU - Woolston, Annemarie
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
PY - 2019/10/1
Y1 - 2019/10/1
N2 - 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.
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.
UR - http://www.scopus.com/inward/record.url?scp=85072848099&partnerID=8YFLogxK
U2 - 10.1038/s41467-019-12441-w
DO - 10.1038/s41467-019-12441-w
M3 - Article
C2 - 31575864
SN - 2041-1723
VL - 10
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 4451
ER -