Investigating Early Kinetics in Plasma ctDNA and Peripheral T-cell Receptor Repertoire to Predict Treatment Outcomes
Enrique Sanz-Garcia1,2, Shirin Soleimani1,3, Jeff P Bruce1
1Princess Margaret Cancer Centre , University Health Network, Toronto, Canada.
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.
Insights
Early monitoring of circulating tumor DNA (ctDNA) and T cell receptor (TCR) repertoires can predict immune checkpoint blockade (ICB) success in head and neck cancer. These biomarkers may guide timely treatment adjustments for recurrent/metastatic HNSCC patients.
Area of Science:
- Oncology
- Immunology
- Biomarker Discovery
Background:
- Immune checkpoint blockade (ICB) targeting the PD-1 axis improves survival in recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC).
- Circulating tumor DNA (ctDNA) and T cell receptor (TCR) repertoires are emerging biomarkers for predicting ICB response.
- Early characterization of ctDNA and TCR dynamics may enable timely treatment adjustments before clinical progression.
Purpose of the Study:
- To investigate the utility of simultaneous early monitoring of ctDNA and TCR dynamics for predicting ICB outcomes in R/M HNSCC.
- To correlate ctDNA and TCR repertoire changes with clinical response, progression-free survival, and overall survival.
- To identify specific TCR signatures associated with clinical benefit and response to ICB therapy.
Main Methods:
- Prospective single-center IO-KIN study (NCT04606940) with 15 R/M HNSCC patients treated with nivolumab or pembrolizumab.
- Collection of 104 blood samples across seven timepoints from baseline to day 29.
- Analysis of ctDNA using personalized Signatera assay and peripheral TCR repertoires using CapTCR-seq in eight patients.
Main Results:
- A decline in ctDNA after day 8 correlated with radiological response, longer progression-free survival, and a trend toward improved overall survival.
- TCR repertoires showed transient diversification between days 8-22, with longer windows in patients with sustained ctDNA decline.
- An Epstein-Barr virus (EBV)-specific TCR signature was identified using GLIPHII and persisted in patients with clinical benefit; additional TCR signatures emerged early 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 highlights the importance of precise sample timing for guiding early therapeutic decisions.
- These findings support the use of ctDNA and TCR dynamics as predictive biomarkers to optimize ICB treatment strategies and improve patient outcomes.
