Investigating Early Kinetics in Plasma ctDNA and Peripheral T-cell Receptor Repertoire to Predict Treatment Outcomes to PD-1 Inhibitors in Head and Neck Squamous Cell Carcinoma.

[PURPOSE] Immune checkpoint blockade (ICB) therapies targeting the PD-1 axis have significantly improved survival in patients with recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). Circulating tumor DNA (ctDNA) and peripheral T-cell receptor (TCR) repertoires are emerging as promising biomarkers for predicting ICB response. Early characterization of ctDNA and TCR dynamics may enable timely treatment adjustments before clinical or radiologic progression.

[EXPERIMENTAL DESIGN] The IO-KIN study (NCT04606940) is a single-center, prospective trial involving 15 patients with R/M HNSCC treated with nivolumab or pembrolizumab. Blood samples (n = 104) were collected across seven time points from baseline to day 29. ctDNA was analyzed using a personalized assay (Signatera), and peripheral TCR repertoires were profiled using CapTCR-seq in eight patients.

[RESULTS] A decline in ctDNA after day 8 was associated with radiologic response, longer progression-free survival, and a trend toward improved overall survival. TCR repertoires transiently diversified between days 8 and 22, with longer diversification windows in patients showing sustained ctDNA decline. Using the GLIPHII algorithm, an Epstein-Barr virus-specific TCR signature was identified and persisted in patients with clinical benefit. Additional TCR signatures, potentially recognizing tumor-associated antigens, emerged as early as day 3 and were linked to positive outcomes.

[CONCLUSIONS] Simultaneous early monitoring of ctDNA and TCR dynamics reveals key determinants of ICB outcomes in R/M HNSCC. The transient nature of TCR diversification emphasizes the importance of precise sample timing to guide early therapeutic decisions and improve patient outcomes.