作者
Sara Ghorashian,Giovanna Lucchini,Rachel Richardson,Kyvi Nguyen,Craig Terris,Aleks Guvenel,Macarena Oporto Espuelas,Jenny Yeung,Danielle Pinner,Jan Chu,Lindsy N. Williams,Ka-Yuk Ko,Chloe Walding,Kelly Watts,Sarah Inglott,Rebecca Thomas,Christopher Connor,Stuart Adams,Emma Gravett,Kimberly C. Gilmour,Alka Lal,Bilyana Popova,Sangeetha Kunaseelan,Andre Lopes,Yenting Ngai,Allan Hackshaw,Evangelia Kokalaki,Milena Balasch-Carulla,Khushnuma Mullanfiroze,Arina Lazareva,Vesna Pavasovic,Anupama Rao,Jack Bartram,Ajay Vora,Robert Chiesa,Juliana M Furtado Silva,Kanchan Rao,Denise Bonney,Robert Wynn,Martin Pulé,Rachael Hough,Persis Amrolia
摘要
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.