To affinity and beyond: harnessing the T cell receptor for cancer immunotherapy.

T cell adoptive therapies for immune-mediated regression of cancers have attracted a great deal of recent attention. Clinical results are glamorous, yet much remains to be uncovered behind the basic science that allows us to engineer T cells and T cell receptors (TCRs) for clinical use. We discuss the development of TCRs for therapeutic use in the context of thymic selection toward central tolerance and we review therapies based on tumor infiltrating lymphocytes (TILs), endogenous antigen specific TCRs, and engineered TCRs. Further we discuss the development of low and high affinity TCRs and the extent to which each challenges central tolerance. Current results suggest that adaptation of TCR engineering of moderate affinity TCRs coupled with co-regulatory and stimulatory molecules may be the safest and most efficacious road for TCR development aimed at tumor abolition.