Article
作者: Richardson, Rachel ; Hough, Rachael ; Hackshaw, Allan ; Connor, Christopher ; Gravett, Emma ; Ko, Ka-Yuk ; Carulla, Milena Balasch ; Rao, Anupama ; Chu, Jan ; Silva, Juliana ; Ngai, Yenting ; Nguyen, Kyvi ; Popova, Bilyana ; Pavasovic, Vesna ; Gilmour, Kimberly ; Guvenel, Aleks ; Thomas, Rebecca ; Terris, Craig ; Mullanfiroze, Khushnuma ; Lucchini, Giovanna ; Lopes, Andre ; Adams, Stuart ; Ghorashian, Sara ; Walding, Chloe ; Lazareva, Arina ; Bonney, Denise ; Pinner, Danielle ; Chiesa, Robert ; Lal, Alka ; Rao, Kanchan ; Inglott, Sarah ; Oporto-Espuelas, Macarena ; Kunaseelan, Sangeetha ; Yeung, Jenny ; Wynn, Robert ; Pule, Martin ; Kokalaki, Evangelia ; Watts, Kelly ; Bartram, Jack ; Amrolia, Persis J. ; Vora, Ajay ; Williams, Lindsey
Abstract:CD19-negative relapse is a leading cause of treatment failure after chimeric antigen receptor (CAR) T-cell therapy for acute lymphoblastic leukemia. We investigated a CAR T-cell product targeting CD19 and CD22 generated by lentiviral cotransduction with vectors encoding our previously described fast-off rate CD19 CAR (AUTO1) combined with a novel CD22 CAR capable of effective signaling at low antigen density. Twelve patients with advanced B-cell acute lymphoblastic leukemia were treated (CARPALL [Immunotherapy with CD19/22 CAR Redirected T Cells for High Risk/Relapsed Paediatric CD19+ and/or CD22+ Acute Lymphoblastic Leukaemia] study, NCT02443831), a third of whom had failed prior licensed CAR therapy. Toxicity was similar to that of AUTO1 alone, with no cases of severe cytokine release syndrome. Of 12 patients, 10 (83%) achieved a measurable residual disease (MRD)–negative complete remission at 2 months after infusion. Of 10 responding patients, 5 had emergence of MRD (n = 2) or relapse (n = 3) with CD19- and CD22-expressing disease associated with loss of CAR T-cell persistence. With a median follow-up of 8.7 months, there were no cases of relapse due to antigen-negative escape. Overall survival was 75% (95% confidence interval [CI], 41%-91%) at 6 and 12 months. The 6- and 12-month event-free survival rates were 75% (95% CI, 41%-91%) and 60% (95% CI, 23%-84%), respectively. These data suggest dual targeting with cotransduction may prevent antigen-negative relapse after CAR T-cell therapy.