Circumventing T-cell tolerance to tumour antigens

During past decades, many attempts have been made to induce or enhance tumour-specific T-cell immunity in cancer patients by vaccination. However, it has become apparent that in a large number of cases the naturally occurring tumour-specific T-cell repertoire is of low affinity and therefore inefficient in mediating tumour rejection. Because of the potential therapeutic value of high affinity TCRs with tumour/lineage specificities, we set out to develop a number of new technologies that can be used to create improved tumour-specific T-cell immunity. These strategies entail: (i) the efficient expansion of low affinity T cells specific for self antigens through the use of variant peptides with improved TCR-binding characteristics; (ii) a retroviral library-based technology to improve the affinity of (self-specific) T-cell receptors in vitro, and (iii) proof of principle for the feasibility of TCR gene transfer as a means to generate T-cell populations with a desired antigen-specificity in vivo. Collectively this toolbox should allow us to create improved T-cell receptors for human tumour antigens, which can subsequently be used to impose tumour-reactivity on to peripheral T cells.