作者
Sara Ghorashian,Anne Marijn Kramer,Shimobi Onuoha,Gary Wright,Jack Bartram,Rachael T. Richardson,Sarah J. Albon,Joan Casanovas-Company,Fernanda Castro,Bilyana Popova,Krystle Villanueva,Jenny Yeung,Winston Vetharoy,Aleks Guvenel,Patrycja Wawrzyniecka,Leila Mekkaoui,Gordon Weng-Kit Cheung,Danielle Pinner,Jan Chu,Giovanna Lucchini,Clóvis A. Silva,Oana Ciocârlie,Arina Lazareva,Sarah Inglott,Kimberly Gilmour,Gulrukh Ahsan,Mathieu Ferrari,Somayya Manzoor,Kim Champion,Tony Brooks,Andre Lopes,Allan Hackshaw,Farzin Farzaneh,Robert Chiesa,Kanchan Rao,Denise Bonney,Sujith Samarasinghe,Nicholas Goulden,Ajay Vora,Paul Veys,Rachael Hough,Robert Wynn,Martin Pulè,Persis Amrolia
摘要
Chimeric antigen receptor (CAR)-modified T cells targeting CD19 demonstrate unparalleled responses in relapsed/refractory acute lymphoblastic leukemia (ALL)1-5, but toxicity, including cytokine-release syndrome (CRS) and neurotoxicity, limits broader application. Moreover, 40-60% of patients relapse owing to poor CAR T cell persistence or emergence of CD19- clones. Some factors, including the choice of single-chain spacer6 and extracellular7 and costimulatory domains8, have a profound effect on CAR T cell function and persistence. However, little is known about the impact of CAR binding affinity. There is evidence of a ceiling above which increased immunoreceptor affinity may adversely affect T cell responses9-11. We generated a novel CD19 CAR (CAT) with a lower affinity than FMC63, the high-affinity binder used in many clinical studies1-4. CAT CAR T cells showed increased proliferation and cytotoxicity in vitro and had enhanced proliferative and in vivo antitumor activity compared with FMC63 CAR T cells. In a clinical study (CARPALL, NCT02443831 ), 12/14 patients with relapsed/refractory pediatric B cell acute lymphoblastic leukemia treated with CAT CAR T cells achieved molecular remission. Persistence was demonstrated in 11 of 14 patients at last follow-up, with enhanced CAR T cell expansion compared with published data. Toxicity was low, with no severe CRS. One-year overall and event-free survival were 63% and 46%, respectively.