Elucidating the Heterogeneity of Immunotherapy Response and Immune-Related Toxicities by Longitudinal ctDNA and
Joseph C Murray1,2,3, Lavanya Sivapalan1, Karlijn Hummelink4
1The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Purpose:
Although immunotherapy is the mainstay of therapy for advanced non-small cell lung cancer (NSCLC), robust biomarkers of clinical response are lacking. The heterogeneity of clinical responses together with the limited value of radiographic response assessments to timely and accurately predict therapeutic effect-especially in the setting of stable disease-calls for the development of molecularly informed real-time minimally invasive approaches. In addition to capturing tumor regression, liquid biopsies may be informative in capturing immune-related adverse events (irAE).
Experimental Design:
We investigated longitudinal changes in circulating tumor DNA (ctDNA) in patients with metastatic NSCLC who received immunotherapy-based regimens. Using ctDNA targeted error-correction sequencing together with matched sequencing of white blood cells and tumor tissue, we tracked serial changes in cell-free tumor load (cfTL) and determined molecular response. Peripheral T-cell repertoire dynamics were serially assessed and evaluated together with plasma protein expression profiles.
Results:
Molecular response, defined as complete clearance of cfTL, was significantly associated with progression-free (log-rank P = 0.0003) and overall survival (log-rank P = 0.01) and was particularly informative in capturing differential survival outcomes among patients with radiographically stable disease. For patients who developed irAEs, on-treatment peripheral blood T-cell repertoire reshaping, assessed by significant T-cell receptor (TCR) clonotypic expansions and regressions, was identified on average 5 months prior to clinical diagnosis of an irAE.
Conclusions:
Molecular responses assist with the interpretation of heterogeneous clinical responses, especially for patients with stable disease. Our complementary assessment of the peripheral tumor and immune compartments provides an approach for monitoring of clinical benefits and irAEs during immunotherapy.
Insights
Molecular response, defined by circulating tumor DNA clearance, predicts survival in advanced non-small cell lung cancer (NSCLC) patients on immunotherapy. This minimally invasive approach also detects immune-related adverse events (irAEs) early.
Area of Science:
- Oncology
- Immunotherapy
- Molecular Diagnostics
Background:
- Immunotherapy is a primary treatment for advanced non-small cell lung cancer (NSCLC).
- Current biomarkers lack robustness for predicting clinical response and therapeutic effects.
- Radiographic assessments have limitations, especially for stable disease, necessitating real-time, minimally invasive monitoring methods.
Purpose of the Study:
- To investigate longitudinal changes in circulating tumor DNA (ctDNA) in metastatic NSCLC patients receiving immunotherapy.
- To correlate ctDNA dynamics with clinical outcomes and immune-related adverse events (irAEs).
- To explore peripheral T-cell repertoire and plasma protein profiles alongside ctDNA.
Main Methods:
- Targeted ctDNA sequencing with error correction was used.
- Serial monitoring of cell-free tumor load (cfTL) and molecular response was performed.
- Peripheral T-cell receptor (TCR) repertoire dynamics and plasma protein expression were assessed.
Main Results:
- Complete ctDNA clearance (molecular response) significantly correlated with improved progression-free and overall survival.
- Molecular response was particularly informative in patients with radiographically stable disease.
- Peripheral T-cell repertoire changes preceded clinical diagnosis of irAEs by approximately 5 months.
Conclusions:
- Molecular response aids in interpreting heterogeneous clinical responses in NSCLC, especially in stable disease.
- Complementary assessment of tumor and immune compartments offers a novel approach for monitoring immunotherapy efficacy and irAEs.
