Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 1 de 1
Filter
Add more filters










Database
Language
Publication year range
1.
Nat Commun ; 10(1): 4451, 2019 10 01.
Article in English | MEDLINE | ID: mdl-31575864

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.


Subject(s)
Antigens/immunology , Cell Engineering , Genes, T-Cell Receptor/genetics , Genes, T-Cell Receptor/immunology , Receptors, Antigen, T-Cell/genetics , Receptors, Antigen, T-Cell/metabolism , T-Lymphocytes/metabolism , Animals , Antigens, CD/metabolism , Antigens, Differentiation, T-Lymphocyte/metabolism , Cell Line, Tumor , Cell Proliferation , Cytokines/metabolism , Gene Expression , Genetic Therapy , Humans , Lectins, C-Type/metabolism , Lymphocyte Activation , Male , Mice , Mice, Inbred NOD , Mice, SCID , Models, Molecular , Protein Domains , Protein Engineering , Receptors, Antigen, T-Cell/chemistry , Receptors, Antigen, T-Cell/immunology , T-Lymphocytes/immunology
SELECTION OF CITATIONS
SEARCH DETAIL
...