Assessing CAR T-cell therapy response using genome-wide sequencing of cell-free DNA in patients with B-cell lymphomas.

Abstract

BACKGROUND\nMethods that enable monitoring of therapeutic efficacy of autologous chimeric antigen receptor (CAR) T-cell therapy will be clinically useful.\n\n\nOBJECTIVES\nThe 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.\n\n\nSTUDY DESIGN\nWhole 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.\n\n\nRESULTS\nTwelve 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 (threshold). Two patients who attained CR, but later relapsed, and all but one patient who had best response other than CR had last GIN measurement of >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).\n\n\nCONCLUSIONS\nThese 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.