Intratumour heterogeneity is associated with poor outcome and acquisition of resistance to cancer therapeutics. Tumour immunotherapy has shown promise with prolonged disease control reported in in several solid tumours. Despite this, many patients with non-small cell lung cancer and Melanoma do not benefit from immunotherapy and have limited treatment options in the advanced disease setting. The Swanton and Quezada groups are developing methods to identify patient cohorts sensitive to checkpoint inhibitor blockade and through the use of peptide vaccination methods, developing clinical trials to enhance therapeutic response to checkpoint inhibitors. Central to this endeavor has been the finding that the burden of neo-antigens in every tumour cell (clonal or trunk neo-antigens) together with a low burden of heterogeneous neo-antigens is predictive of response to checkpoint blockade and patients with a high clonal neo-antigen burden have a superior outcome than patients with NSCLC with a low clonal and heterogeneous neo-antigen burden. Consistent with the importance of clonal neo-antigens, we have identified cytotoxic T cells reactive against clonal neo-antigens. We are now attempting to optimize our methods for the detection of clonal neo-antigens through RNA-seq analysis of a large longitudinal lung cancer evolution cohort, TRACERx in order that better methods can be devised to leverage the host immune system against tumour neo-antigens present in every tumour cell in order to attempt to enhance tumour control and cancer survival outcomes.