Display, engineering, and applications of antigen-specific T cell receptors

The use of T cell receptors (TCRs) as potential therapeutic agents provides an opportunity to target a greatly expanded array of antigens, compared to those now targeted with monoclonal antibodies. With the advent of new display technologies and TCR formats for in vitro engineering, it should be possible to generate high-affinity TCRs against virtually any peptide antigen that is shown to bind to a major histocompatibility complex (MHC) molecule (e.g. peptides derived from viral antigens or from self proteins that are associated with the transformed phenotype). What remains, however, are challenges associated with effective targeting of very low numbers of cell surface antigens (pepMHC), fewer than the case for conventional monoclonal antibody-based therapies. This hurdle might be overcome with the attachment of more effective payloads for soluble TCR approaches, or by using TCR gene transfer into T cells that can then be adoptively transferred into patients. There is considerable work to be done on the physiological aspects of either approach, including pharmacokinetic studies in the case of soluble TCRs, and T cell trafficking, persistence, and autoreactivity studies in the case of adoptively transferred T cells. As with the field of monoclonal antibodies, it will take time to explore these issues, but the potential benefits of TCR-based therapies make these challenges worth the effort.