Monitoring Immunotherapy Response via Gene Silencing Landscapes in Cell-Free DNA

ABSTRACT:
Immunotherapies produce remarkable, long-term responses in subsets of patients with non-small cell lung
cancer, but unfortunately, most patients do not respond to such treatment. Current biomarkers to predict which
patients will benefit have limited accuracy, and decisions to continue or suspend treatment are mainly guided by
monitoring of radiographic changes in tumor size. However, unusual immune-related response patterns such
as pseudo-progression, mixed response, and delayed response can make scans difficult to interpret. Circulating
tumor DNA (ctDNA) has emerged as a highly promising biomarker for monitoring immunotherapy efficacy.
Several studies involving various immunotherapy agents and multiple types of cancer have demonstrated that
early reduction in ctDNA levels during treatment are predictive of tumor response and improved survival
outcomes. However, existing technologies that measure ctDNA by probing for common somatic mutations will
fail in patients whose tumors lack these mutations. This limitation is being addressed by creating customized
assays based on patient-specific tumor mutation profiles; but this approach is complex, expensive, and slow.
We have developed a ctDNA assay technology based on detection of epigenetic features that are found in
virtually all cancer cell genomes. Our Phase I data indicate that our approach has broad patient coverage and
can be applied to multiple types of cancer without requiring tumor profiling and assay customization. In this
Phase II project, we aim to build data to support the clinical utility of our assay technology for monitoring of lung
cancer immunotherapy response. We also aim to advance our current research-mode assay to rigorous clinical-
grade testing standards for use in clinical practice.

Grant Number: 5R44CA285041-03
NIH Institute/Center: NIH
Principal Investigator: Michael Barrett