Investigating Early Kinetics in Plasma ctDNA and Peripheral T Cell Receptor Repertoire to Predict Treatment Outcomes to PD-1 Inhibitors
PD-1:PD-L1 axis targeting immune checkpoint blockade (ICB) significantly improves survival in patients with recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). Circulating tumor DNA (ctDNA) and peripheral T cell receptor (TCR) repertoires are emerging as potential predictive biomarkers of response to ICB and understanding their early dynamics during treatment could guide treatment adjustments before progression is evident radiologically. IO-KIN (NCT04606940) is a prospective study of R/M HNSCC patients treated with nivolumab or pembrolizumab. 104 blood samples were collected across 7 time points, spanning baseline and the first 29 days after the initial ICB dose. We examined the early dynamics of ctDNA (N = 15 patients), and the peripheral TCR repertoire (N = 8 patients). While baseline ctDNA levels did not correlate with clinical outcomes, a decrease in ctDNA after day 8 was associated with clinical benefit, prolonged progression-free survival, and a trend toward improved overall survival. TCR repertoire transiently diversified in response to ICB, peaking between days 8-22. GLIPHII (Grouping Lymphocyte Interactions by Paratope Hotspots II) analysis identified signatures recognizing tumor-associated antigens at baseline and emerging in response to ICB as early as three days. We demonstrated that simultaneous monitoring of ctDNA and TCR dynamics during treatment allows for more personalized and timely treatment strategies.
Head and Neck Squamous Cell Carcinoma (HNSCC), Recurrent/Metastatic (R/M), Immune Checkpoint Blockade (ICB), Circulating Tumor DNA (ctDNA), T-Cell Receptor (TCR), Peripheral Blood
Input data to generate figure 1B Tile plot.
Clinical data for IO-KIN patients.
Buffy coat CapTCR-seq processed data for 8 IO-KIN patients that were serially collected at baseline (same or prior day to first ICB dose administration), days 2, 3, 8, 15, 22, and 29 post-infusion;
TRB-CDR3 sequences were assembled using MiXCR 3.0.12.
ctDNA levels provided by SignateraTM, Natera.
Diversity indices (including Richness, Shannon diversity, and higher-order indeices) representing the clonal structure of the buffy coat TCR repertoires.
Shannon and Simpson clonality indices of the buffy coat TCR repertoires.
These indices were not reported in the paper.
Raw data generated by GLIPHII algorithm.
HLA genotypes for each of IO-KIN patients.
An igraph network representing TRB-CDR3 sequences (nodes) connected by GLIPH-II identified global or local specificity signatures (edges, indicated by the 'type' field in the GLIPH-II output). This network is the result of graph-based filtering, including criteria such as community size and node connectivity determined by clique formation. HLA convergence criteria have not been applied to generate this network.
A dataframe summarizing GLIPHII specificity community features prior to applying HLA convergence filtration criteria.
This network is a simplified version of 09_IOKIN_GLIPHIINetwork_PreHLAConvergence.rds, designed for improved visualization and interpretability. Individual TRB-CDR3 nodes that belong to the same GLIPHII-defined specificity community are collapsed into a single supernode. Therefore, each supernode represents a unique specificity community, rather than an individual TRB-CDR3 sequence. This supernode representation provides a more manageable and visually accessible overview of the overall landscape of specificity communities.
HLA-filtered version of 09_IOKIN_GLIPHIINetwork_PreHLAConvergence.rds
HLA-filtered version of 10_IOKIN_GLIPHIICommunityFeatures_PreHLAConvergence.csv
HLA-filtered version of 11_IOKIN_GLIPHIISuperNodes_PreHLAConvergence.rds
R version 4.4.1 (2024-06-14) Running under: macOS Big Sur 11.7.10
RStudio Version 2023.09.1+494
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Package igraph version 2.1.4
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