Tumor-intrinsic causes of CAR-T failure

In this issue of Blood, two reports delineate tumor-specific factors associated with clinical responses to infusion of approved T-cell products genetically modified with a chimeric antigen receptor (CAR) targeting CD19 in patients with diffuse large B-cell lymphoma (DLBCL)1,2 (see figure). Jain et al comprehensively characterized the genomes of lymphoma tissue from patients who received CD19 CAR-T cells and report that genome-wide mutational signatures and patterns of structural alterations are associated with CAR-T cell response. Cherng et al evaluated circulating tumor DNA and show that a high focal copy number alterations (CNAs) score, denoting genomic instability, was the most significant pretreatment variable associated with poor response to CAR-T therapy or subsequent relapse.