Characterization and optimization of T cell/antigen interactions (360G-Wellcome-086716_Z_08_Z)

T-cells recognise 'foreign' peptides bound to self-major histocompatibility complex (pMHC) molecules with their specific T-cell receptors (TCRs) and are critical for the elimination of pathogen-infected and tumour cells. Our preliminary data indicates that while natural T-cell receptors (TCRs) may be the best available solution for recognition of a particular antigen they are far from the best possible solution. We have produced T-cells that the HIV virus cannot escape from and manufactured TCRs that are 100 times better than the best natural TCRs at recognizing human cancer antigens when transduced into primary human T-cells. Our objectives are to: (1) Produce TCRs to a range of pathogen- and cancer-specific peptide antigens (2) Build optimized vehicles for expression of TCRs in T-cells without TCR chain mispairing (3) Determine the optimal TCR binding affinity, kinetics and glycosylation status for antigen recognition (4) Produce and characterize optimal epitopes for a range of natural T-cells (5) Optimize interactions between the MHC and T-cell coreceptors We are working with groups from around the globe that wish to apply this knowledge to new therapeutic approaches to cancer and infection by the adoptive transfer of patient-autologous T-cells, or 'immortalized' human killer T-cell lines, expressing optimized antigen-specific TCRs.