Avidity optimization of a MAGE‐A1‐specific TCR with somatic hypermutation

A T-cell receptor (TCR) with optimal avidity to a tumor antigen can be used redirect T cells eradicate cancer via adoptive cell transfer. Cancer testis antigens (CTAs) are attractive targets because they expressed in the testis, which is immune-privileged, and tumor. However, CTAs self-antigens natural TCRs have low affinity/avidity due central tolerance. We previously described method of directed evolution TCR using somatic hypermutation. In this study, we made several improvements enhanced hT27 TCR, specific for HLA-A2-MAGE-A1278-286. identified eight point mutations varying degrees improved avidity. Human transduced containing these displayed tetramer binding, IFN-γ IL2 production, cytotoxicity. Most retained specificity, except one mutant extremely high demonstrate that hypermutation capable optimizing clinically relevant immunotherapy.