Abstract

Low Coverage, Genome-Wide Sequencing of Cell-free DNA Enables the Monitoring of Response to Immunotherapy in Cancer Patients

Taylor Jensen, Director, Research and Development, Sequenom

Inhibitors of the PD-1/PD-L1/CTLA4 immune checkpoint pathway have revolutionized cancer treatment with a subset of patients showing durable responses; however, challenges remain in the development of biomarkers to predict or monitor response to these therapies.  The use of cell-free DNA (cfDNA) isolated from plasma, or liquid biopsy, provides a promising method for monitoring response.  In contrast to methods that use ultra-deep (>30,000X) targeted sequencing, we will describe a recently completed a proof-of-concept study using low-coverage (~0.3X), genome-wide sequencing of cfDNA to detect tumor-specific copy number alterations.  As part of this study, we have developed a novel metric, the Genome Instability Number (GIN), to monitor response to these drugs throughout treatment.  In a series of case studies, we will describe how the GIN can be used to discriminate clinical response from progression, differentiate progression from pseudoprogression and identify hyperprogressive disease.  In addition, we have utilized this metric to provide evidence for a delayed pharmacokinetic response for checkpoint inhibitors relative to targeted therapies.