HLA-agnostic T-cell Targeting of Cancer

Adoptive transfer of patient T-cells expressing cancer-targeting chimeric antigen receptors (CARs) has achieved remarkable success with some soluble tumours. Unfortunately, CAR-T therapy cannot treat solid tumours. Contrastingly, tumour-infiltrating lymphocyte and checkpoint inhibitor therapies demonstrate that natural T-cells can eradicate end-stage solid cancers in some patients raising interest in engineering T-cells with T-cell receptors (TCRs) for “TCR-T” therapy. Conventional anticancer TCRs recognise endogenous proteinaceous antigens as short peptides presented by human leukocyte antigen class I (HLA-I) allowing killer T-cells to scan the internal proteome and eliminate cells bearing anomalies associated with cancerous transformation. Unfortunately, even the best conventional TCR approaches are only applicable in a minority of patients due to substantial variation in HLA across the population. The ultimate TCR-T therapy would bypass HLA-restriction to enable targeting of shared cancer antigens in all individuals. Our recent discoveries that some T-cells can recognise multiple types of cancer without the need for HLA could represent a major advance for immunotherapies. I want to understand the molecular mechanisms by which such ‘HLA-agnostic’ T-cells recognise cancer and utilise these remarkable cells to identify the cell surface changes that distinguish normal from cancerous cells. These potential cancer-biomarkers and cognate TCRs could underpin novel, broad-spectrum immunotherapies.