Expanded antigen-specific donor regulatory T cells for GVHD prevention
Abstract
Minor histocompatibility antigen (mHAg)-specific alloreactive donor T cells cause graft vs. host disease (GVHD) in matched related donor allogeneic hematopoietic cell transplantation (HCT). In a phase I trial, we expanded and infused (on day -2) mHAg-specific donor regulatory T cells (Treg) together with sirolimus-based pharmacologic prophylaxis to examine safety and preliminary efficacy of this GVHD prevention approach. We employed a 3+3 phase I design escalating Treg dose in 4 levels: 0.5 x 105/kg, 1 x 105/kg, 2 x 105/kg, and 4 x 105/kg. Dose-limiting toxicity (DLT) included grade 4-5 related infusion reaction, grade 4-5 unexpected organ toxicity, grade III-IV acute GVHD, or treatment-related death. Secondary and exploratory measures examined acute and chronic GVHD, survival outcomes, and Treg clone (TCR-Seq) expansion in culture, and in-vivo longevity and expansion post-HCT. 15 subjects were included (N=3 each per dose levels 1-3, and N=6 in dose level 4). No DLT were observed, and 4 x 105/kg Treg was identified as MTD. Median follow up for survivors was 41.7 months (range 14.5-72.8). The day 100 cumulative incidence of grade II-IV acute GVHD was 13% (95% CI 2-35%). NIH moderate/severe chronic GVHD by 1 year was 6.7% (95% CI 0.36-27%) and by 3 years was 20% (95%CI 4.4-44%). Overall survival was 73% (95% CI 54-100%). Treg clones expanded in culture, and demonstrated post-HCT lineage fidelity, persistence, and in-vivo expansion. This translational trial supports mHAg-specific expanded donor Treg as a novel GVHD prevention strategy, and demonstrates expanded donor Treg clones can persist and expand through one-year post-HCT. NCT01795573
Article Details
Authors (38)
Joseph A Pidala
H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, United States
Nicoletta Cieri
Dana-Farber Cancer Institute, Boston, Massachusetts, United States
Michael J Schell
Moffitt Cancer Center, Tampa, Florida, United States
Xiaofei Song
Molecular Synthesis Center, Key Laboratory of Marine Drugs of Ministry of Education, Shandong Key Laboratory of Glycoscience and Glycotherapeutics, School of Medicine and Pharmacy
Yiren Shao
Dana-Farber Cancer Institute, Boston, Massachusetts, United States
Biwei Cao
Moffitt Cancer Center, Tampa, Florida, United States
Dongliang Du
H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, United States
Ram Thapa
Moffitt Cancer Center, Tampa, Florida, United States
Brian C Betts
Roswell Park Comprehensive Cancer Center, Buffalo, New York, United States
William Janssen
Christopher Cubitt
Sean J Yoder
Moffitt Cancer Center and Research Institute, Tampa, Florida, United States
Mandy Flannery O'Leary
Moffitt Cancer Center, Tampa, Florida, United States
Francisca Beato
H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, United States
Anandharaman Veerapathran
Moffitt Cancer Center, Acton, Massachusetts, United States
Meghan A Menges
Moffitt Cancer Center, Tampa, Florida, United States
Michelle Burton
Moffitt Cancer Center, Tampa, Florida, United States
Nelli Bejanyan
Moffitt Cancer Center, Tampa, Florida, United States
Omar Alexis Castaneda-Puglianini
H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, United States
Hany Elmariah
Stanford University, Stanford, California, United States
Rawan G. Faramand
Hugo F. Fernandez
H. Lee Moffitt Cancer Center, Pembroke Pines, Florida, United States
Doris K Hansen
H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, United States
Michael D Jain
Moffitt Cancer Center, Tampa, Florida, United States
Farhad Khimani
H. Lee Moffitt Cancer Center, Tampa, Florida, United States
Aleksandr Lazaryan
Moffitt Cancer Center, Tampa, Florida, United States
Hien D Liu
H.Lee Moffitt Cancer Center, Tampa, Florida, United States
Frederick L. Locke
Abu-Sayeef Mirza
6Moffitt Cancer Center, Tampa, FL
Asmita Mishra
H. Lee Moffitt Cancer Center and Research Institute, TAMPA, Florida, United States
Michael Nieder
Moffitt Cancer Center, Tampa, Florida, United States
Taiga Nishihori
Moffitt Cancer Center, Tampa, Florida, United States
Leonel Ochoa
Moffitt Cancer Center
Lia E Perez
H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, United States
Fabiana Perna
Moffitt Cancer Center, Tampa, Florida, United States
Reshma Ramlal
Moffitt Cancer Center, Tampa, Florida, United States
Nancy Eunice Torres
H Lee Moffitt Cancer Center, Tampa, Florida, United States
Claudio Anasetti
H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, United States