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

Abstract

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.

Phase 2 study of axicabtagene ciloleucel in Japanese patients with relapsed or refractory large B-cell lymphoma

“…Finding biomarkers that can predict efficacy of axi-cel is important for patient stratification. Patients characteristic and/or product characteristics have been studied using ZUMA-1 data [17,18]. It was suggested that low tumor Fig.…”

“…Finding biomarkers that can predict efficacy of axi-cel is important for patient stratification. Patients characteristic and/or product characteristics have been studied using ZUMA-1 data [ 17 , 18 ]. It was suggested that low tumor burden, low systemic inflammation, and high product CCR7 + CD45RA + T cells were associated with durable responses [ 17 ].…”

Born to survive: how cancer cells resist CAR T cell therapy

“…CD19-negative relapses seem to be associated with high tumor burden at the time of lymphodepletion [ 11 ]. In DLBCL, approximately a third of relapses exhibit CD19 loss or downregulation [ 12 – 18 ]. Importantly, CD19-negative or -low leukemia or lymphoma cells retain expression of other B cell markers such as CD22 for B-ALL, CD20 and CD79a for lymphoma [ 18 ].…”

“…In DLBCL, approximately a third of relapses exhibit CD19 loss or downregulation [ 12 – 18 ]. Importantly, CD19-negative or -low leukemia or lymphoma cells retain expression of other B cell markers such as CD22 for B-ALL, CD20 and CD79a for lymphoma [ 18 ]. In MCL, Wang and colleagues reported 14 (23%) relapses among the 60 patients in the primary efficacy analysis of the ZUMA-2 trial, of which 1 (7%) had undetectable CD19 at relapse [ 19 ].…”

T-cell Redirecting Therapies for the Treatment of B-cell Lymphomas: Recent Advances

“…Approximately a third of DLBCL relapses exhibit CD19 loss or down-regulation after CAR T-cell therapy [29]. Bispecific CAR T-cells have been developed to prevent or reduce the risk of immune escape by loss of target antigen.…”