Assessing CAR T-Cell Therapy Response Using Genome-Wide Sequencing of Cell-Free DNA in Patients With B-Cell Lymphomas.

Abstract Background Methods that enable monitoring of therapeutic efficacy of autologous chimeric antigen receptor (CAR) T-cell therapy will be clinically useful. Objectives The aim of this study is to demonstrate the feasibility of blood-derived cell-free DNA (cfDNA) to predict CAR T-cell therapy response in patients with refractory B-cell lymphomas. Study design Whole blood was collected prior to and throughout CAR T-cell therapy until day +154. Low-coverage (∼0.4X), genome-wide cfDNA sequencing, similar to that established for non-invasive prenatal testing, was performed. The genomic instability number (GIN) was utilized to quantify plasma copy number alteration level. Results Twelve patients were enrolled. Seven (58%) patients achieved a complete response (CR); 2 (25%), a partial response. Median progression-free survival was 99 days; median overall survival not reached (median follow up, 247 days). Altogether, 127 blood samples were analyzed (median, 10 samples/patient (range 8-13)). All five patients who remained in CR at the time of last measurement had GIN 170. In five of six patients with relapsed or progressive disease, increasing GIN was observed prior to the diagnosis by imaging. The abundance of CAR T-cell construct (absolute number of construct copies relative to the number of human genome equivalents) also showed a trend to correlate with outcome (day 10, p=0.052). Conclusions These data describe a proof-of-concept for the use of multiple liquid biopsy technologies to monitor therapeutic response in B-cell lymphoma patients receiving CAR T-cell therapy.