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

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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.

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