Dynamic immune profiling predicts response to radiation plus anti-PD-1 therapy in oligometastatic renal cell...

Biomarkers that predict response to combined radiation and anti-PD-1 therapy in clear cell renal cell carcinoma (ccRCC) are poorly defined. RAPPORT trial (NCT02855203) is a prospective phase I/II study of stereotactic ablative body radiotherapy (SABR) and pembrolizumab in 30 patients with oligometastatic ccRCC. The primary endpoint was safety; secondary endpoints included overall survival, time to local progression, distant progression-free survival, objective and disease control rates, duration of response and patient-reported pain. Here, we report the pre-specified exploratory translational analyses. In pre-treatment tumours, responders had greater intra-tumoural cytotoxic T cell infiltration in close proximity to tumour cells, whereas non-responders showed enrichment of immunosuppressive, TGF-β and angiogenic signatures. In peripheral blood post-treatment, responders developed a proliferative burst of activated CD8⁺ T cells and sustained sharing of pre-existing tumour-enriched TCR clones. These findings identify trafficking and maintenance of pre-existing tumour-enriched T cell clones as determinants of response to SABR plus anti-PD-1 in ccRCC.