TCR Off-Target Assessment
In T cell receptor (TCR) therapy, a patient’s own T cells are removed from the body, engineered to recognise tumour-specific antigens by expressing genetically engineered high-affinity TCRs, and then injected back into the body. In contrast to CAR-T therapies that recognise proteins expressed on cell surfaces, TCR therapies have the potential to treat solid cancers since they can target intracellular antigens.
However, clinical trials for TCR therapies have raised serious concerns about off-target toxicities that destroy healthy tissue and may even result in death. Toxicities due to undesired cross reactivity of TCRs with target peptide/MHC complexes highlight the urgency of pre-clinical testing to assess which peptides can be recognised by a TCR.
For example, a soluble, affinity-matured TCR targeting a MAGE3-derived peptide presented by A*0101 was shown to cross react with a titin-derived peptide resulting in cardiac arrest and death in two patients during clinical trial. (https://pubmed.ncbi.nlm.nih.gov/23926201/)
Immunitrack has the technology to assess TCR off-target effects by screening positional scanning libraries derived from target peptides using flow cytometry or ELISA. Here, the target peptide e.g., a tumour-specific antigen, is substituted with all amino acids at given positions and the resulting peptides are screened, individually complexed with MHC I, for interaction with TCRs of interest.