Abstract
T-cell receptor (TCR) therapy has arrived as a realistic treatment option for many human diseases. TCR gene therapy allows for the mass redirection of T-cells against a defined antigen while high affinity TCR engineering allows for the creation of a new class of soluble drugs. However, deciding which TCR blueprint to take forward for gene therapy or engineering is difficult. More than one quintillion TCR combinations can be generated by somatic recombination and we are only now beginning to appreciate that not all are functionally equal. TCRs can exhibit high or low degrees of HLA-restricted cross-reactivity and alloreact against one or a combination of HLA alleles. Identifying TCR candidates with high specificity and minimal cross-reactivity/alloreactivity footprints before engineering is obviously highly desirable. Here we will summarize what we currently know about TCR biology with regard to immunoengineering.