CD19 target evasion as a mechanism of relapse in large B-cell lymphoma treated with axicabtagene ciloleucel

Although anti-CD19 chimeric antigen receptor (CAR) T-cell therapy produces high response rates and durable remissions in patients with large B-cell lymphoma (LBCL), relapses can still occur by mechanisms that are incompletely elucidated. We examined the CD19 antigen characteristics of pretreatment (n=100) and post-relapse (n=20) tumor biopsies from patients treated with axicabtagene ciloleucel (axi-cel) in the multicenter phase 1/2 ZUMA-1 study (NCT02899052). CD19 target antigen expression was variable at baseline and a subset of evaluable patients who relapsed after axi-cel CAR T-cell therapy (~30%) had CD19-low or negative tumors. By comparison CD20, CD22, and CD79a were mostly present at relapse, including in tumors with low CD19 levels. Transcriptomic analysis revealed that the observed impact to antigen levels in a subset of tumor biopsies at relapse was primarily attributed to low or absent CD19 protein expression that was unrelated to alternative splicing events and mutations in CD19, which were also observed. The emergence of tumor cells with low or no CD19 antigen expression are thought to drive the relapse process in some patients, in the context of targeted removal of antigen-positive tumor cells by the therapy. These findings support multi-antigen targeting CAR approaches to improve clinical outcomes in patients with LBCL.