MBP scientist Dr. Trevor Pugh has led a team of researchers, which includes MBP scientists Dr. Scott Bratman and Dr. Benjamin Haibe-Kains in the publication of a new Nature article entitled ‘Pan-cancer analysis of longitudinal metastatic tumors reveals genomic alterations and immune landscape dynamics associated with pembrolizumab sensitivity’
Article Abstract
Serial circulating tumor DNA (ctDNA) monitoring is emerging as a non-invasive strategy topredict and monitor immune checkpoint blockade (ICB) therapeutic efficacy across cancertypes. Yet, limited data exist to show the relationship between ctDNA dynamics and tumorgenome and immune microenvironment in patients receiving ICB. Here, we present an in-depth analysis of clinical, whole-exome, transcriptome, and ctDNA profiles of 73 patientswith advanced solid tumors, across 30 cancer types, from a phase II basket clinical trial ofpembrolizumab (NCT02644369) and report changes in genomic and immune landscapes(primary outcomes). Patients stratified by ctDNA and tumor burden dynamics correspondwith survival and clinical benefit. High mutation burden, high expression of immune sig-natures, and mutations inBRCA2are associated with pembrolizumab molecular sensitivity,while abundant copy-number alterations andB2Mloss-of-heterozygosity corresponded withresistance. Upon treatment, induction of genes expressed by T cell, B cell, and myeloid cellpopulations are consistent with sensitivity and resistance. We identified the upregulatedexpression ofPLA2G2D, an immune-regulating phospholipase, as a potential biomarker ofadaptive resistance to ICB. Together, thesefindings provide insights into the diversity ofimmunogenomic mechanisms that underpin pembrolizumab outcomes.
