Tracking Neoantigens by Personalized Circulating Tumor DNA Sequencing during Checkpoint Blockade Immunotherapy in
Qingzhu Jia1,2, Luting Chiu3, Shuangxiu Wu3
1Institute of Cancer Xinqiao Hospital The Army Medical University Xinqiao Main Street Chongqing 400037 China.
Abstract:
The evolutionary dynamics of tumor-associated neoantigens carry information about drug sensitivity and resistance to the immune checkpoint blockade (ICB). However, the spectrum of somatic mutations is highly heterogeneous among patients, making it difficult to track neoantigens by circulating tumor DNA (ctDNA) sequencing using "one size fits all" commercial gene panels. Thus, individually customized panels (ICPs) are needed to track neoantigen evolution comprehensively during ICB treatment. Dominant neoantigens are predicted from whole exome sequencing data for treatment-naïve tumor tissues. Panels targeting predicted neoantigens are used for personalized ctDNA sequencing. Analyzing ten patients with non-small cell lung cancer, ICPs are effective for tracking most predicted dominant neoantigens (80-100%) in serial peripheral blood samples, and to detect substantially more genes (18-30) than the capacity of current commercial gene panels. A more than 50% decrease in ctDNA concentration after eight weeks of ICB administration is associated with favorable progression-free survival. Furthermore, at the individual level, the magnitude of the early ctDNA response is correlated with the subsequent change in tumor burden. The application of ICP-based ctDNA sequencing is expected to improve the understanding of ICB-driven tumor evolution and to provide personalized management strategies that optimize the clinical benefits of immunotherapies.
Insights
Individually customized panels (ICPs) effectively track tumor neoantigens from circulating tumor DNA (ctDNA) during immune checkpoint blockade (ICB) therapy. This personalized approach improves monitoring of cancer evolution and treatment response.
Area of Science:
- Oncology
- Immunotherapy
- Genomics
Background:
- Tumor-associated neoantigens provide insights into immune checkpoint blockade (ICB) drug sensitivity and resistance.
- Patient-specific somatic mutation heterogeneity complicates neoantigen tracking using standard gene panels.
- Circulating tumor DNA (ctDNA) sequencing requires tailored approaches for comprehensive neoantigen monitoring.
Purpose of the Study:
- To evaluate the efficacy of individually customized panels (ICPs) for tracking neoantigen evolution during ICB treatment.
- To assess the correlation between ctDNA dynamics and clinical outcomes in non-small cell lung cancer (NSCLC) patients.
- To explore the potential of ICP-based ctDNA sequencing for personalized cancer management.
Main Methods:
- Prediction of dominant neoantigens from whole exome sequencing of treatment-naïve tumors.
- Design and application of ICPs for personalized ctDNA sequencing in serial peripheral blood samples.
- Analysis of ctDNA concentration changes and correlation with progression-free survival and tumor burden.
Main Results:
- ICPs successfully tracked 80-100% of predicted dominant neoantigens in NSCLC patients undergoing ICB.
- ICPs detected significantly more genes (18-30) compared to commercial panels.
- A >50% decrease in ctDNA concentration after eight weeks of ICB correlated with favorable progression-free survival.
Conclusions:
- ICP-based ctDNA sequencing is effective for comprehensive neoantigen tracking during ICB therapy.
- Early ctDNA response magnitude predicts subsequent changes in tumor burden at the individual level.
- This personalized sequencing strategy can enhance understanding of ICB-driven tumor evolution and optimize immunotherapy clinical benefits.
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