Results From First-in-Human Phase I Study of a Novel CD19-1XX Chimeric Antigen Receptor With Calibrated Signaling in Large B-Cell Lymphoma
Abstract
PURPOSE We designed a CD19-targeted chimeric antigen receptor (CAR) comprising a calibrated signaling module, termed 1XX, that differs from that of conventional CD28/CD3ζ and 4-1BB/CD3ζ CARs. Preclinical data demonstrated that 1XX CARs generated potent effector function without undermining T-cell persistence. We hypothesized that 1XX CAR T cells may be effective at low doses and elicit minimal toxicities. METHODS In this first-in-human, phase I, dose escalation and expansion clinical trial, patients with relapsed or refractory large B-cell lymphoma received 19(T2)28z-1XX CAR T cells at four dose levels (DLs), ranging from 25 to 200 × 10 6 . RESULTS Twenty-eight patients underwent apheresis and received CAR T cells. Sixteen and 12 patients were treated in the dose escalation and expansion cohorts, respectively. The overall response rate (ORR) was 82% and complete response (CR) rate was 71% in the entire cohort. The lowest dose of 25 × 10 6 was selected for dose expansion. In 16 patients treated at this DL, 88% achieved ORR and 75% CR. With the median follow‐up of 24 months, the 1-year event-free survival was 61% (95% CI, 45 to 82) and 14 patients remain in continuous CR beyond 12 months. In all cohorts, grade ≥3 cytokine release syndrome and immune effector cell–associated neurotoxicity syndrome rates were low at 4% and 7%, respectively. 1XX CAR T-cell products contain a higher proportion of CD8 T cells with memory features, and CAR T-cell persistence has been detected beyond 1-2 years in patients with ongoing remission. CONCLUSION The calibrated potency of the 1XX CAR affords excellent efficacy at low cell doses with favorable toxicity profiles and may benefit the treatment of other hematologic malignancies, solid tumors, and autoimmunity.
Article Details
Journal Info
Journal of Clinical Oncology
Lippincott Williams & Wilkins
Authors (34)
Jae H. Park
M. Lia Palomba
5Memorial Sloan Kettering Cancer Center, New York, NY
Karlo Perica
Sean M. Devlin
Department of Epidemiology & Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY
Gunjan Shah
2Memorial Sloan Kettering Cancer Center, Cellular Therapy Service, Department of Medicine, New York, United States
Parastoo B. Dahi
1Adult Bone Marrow Transplantation Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
Richard J. Lin
Cellular Therapy Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
Gilles Salles
41Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, NY
Michael Scordo
Cellular Therapy Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York
Karthik Nath
Cellular Therapy Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
Yannis K. Valtis
22Cell Therapy Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
Alec Lynch
Cellular Therapy Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
Elizabeth Cathcart
Cellular Therapy Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
Honglei Zhang
Heiko Schoder
1memorial Sloan Kettering, NYC, United States
Doris Leithner
Molecular Imaging and Therapy Service, Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY
Kelly Liotta
Cellular Therapy Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
Alina Yu
Cellular Therapy Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
Kelsey Stocker
Cellular Therapy Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
Jia Li
Agnish Dey
Takeda Pharmaceuticals America, Inc., Cambridge, MA
Leopold Sellner
1Takeda Development Center Americas, Inc. (TDCA), Oncology Therapeutic Area Unit, Cambridge, United States
Reshma Singh
Takeda Development Center Americas, Inc, Cambridge, MA
Varsha Sundaresan
11Takeda Development Center Americas, Inc. (TDCA), Cambridge, United States
Xin Tong
Faye Zhao
Takeda Development Center Americas, Inc, Cambridge, MA
Jorge Mansilla-Soto
Changhao He
Weill Cornell Medical College, New York, NY
Joel Meyerson
Kinga Hosszu
Memorial Sloan Kettering Cancer Center, New York, New York, United States
Devin McAvoy
Sloan Kettering Institute, New York, New York, United States
Xiuyan Wang
Isabelle Rivière
Center for Cell Engineering, Sloan Kettering Institute, New York, NY
Michel Sadelain