Discovery of a novel genomic alteration that renders leukemic cells resistant to CD19-targeted immunotherapies

Abstract

CD19-targeted immunotherapies that stimulate a cytotoxic T-cell response have revolutionized the management of B-cell malignancies, specifically relapsed or refractory acute lymphoblastic leukemia (R/ R ALL). Blinatumomab is an anti-CD19 bispecific T-cell engager approved for the treatment of patients with R/R ALL. 1 KTE-X19 is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy under investigation in the ZUMA-3 (XXX) phase 1/2 clinical trial (registered at www.clinicaltrials.gov as #NCT02614066) for adult patients with R/R ALL. 2 The emergence of leukemic clones that have lost surface expression of CD19 is a cause of disease relapse in 10% to 25% of patients treated with either blinatumomab or CAR T cells. [1][2][3][4][5] Several distinct mechanisms have been documented, including truncating mutations in the transmembrane domain of CD19 that prevent surface expression, 5 as well as alternative messenger RNA splicing that results in loss of the antigenic epitope and prevents CAR binding. 3,4 Here we describe the discovery of a novel genomic modification outside of the transmembrane and antigenic domains of CD19 that enable resistance to blinatumomab and KTE-X19.A 60-year-old woman with B-cell ALL was treated with chemotherapy followed by 2 cycles of blinatumomab as initial therapy. She experienced disease relapse after the second cycle of blinatumomab and was enrolled in the ZUMA-3 investigational study of KTE-X19. She received a single infusion of anti-CD19 CAR T cells at the target dose but had no disease response.