Donor regulatory T-cell therapy to prevent graft-versus-host disease
Abstract
Abstract Allogeneic hematopoietic cell transplantation is a curative therapy limited by graft-versus-host disease (GVHD). In preclinical studies and early-phase clinical studies, enrichment of donor regulatory T cells (Tregs) appears to prevent GVHD and promote healthy immunity. We enrolled 44 patients in an open-label, single-center, phase 2 efficacy study investigating if a precision selected and highly purified Treg therapy manufactured from donor-mobilized peripheral blood improves 1-year GVHD-free relapse-free survival (GRFS) after myeloablative conditioning. We compared this study arm with a concomitant standard-of-care (SOC) cohort. All donor Treg products were successfully manufactured and administered without cryopreservation within 72 hours. Participants had a 1-year incidence of acute grade 3 to 4 GVHD of 7%, moderate to severe chronic GVHD of 11%, and nonrelapse mortality rate of 4.5%. The primary end point of significantly improved 1-year GRFS was achieved at 64% evaluated against a predicted incidence of 40% (P = .002) with a realized incidence of 36% in the SOC comparator. For those trial patients who developed grade 2 to 4 acute GVHD, 91% responded to front-line corticosteroid therapy, whereas 50% responded in the SOC comparator group. Trial participants had a reduced incidence and burden of GVHD and improved GRFS, compared with rates common to highly variable unmanipulated donor grafts and multiagent immune suppression. This trial was registered at www.clinicaltrials.gov as #NCT01660607.
Article Details
Authors (28)
Everett H. Meyer
1Division of Blood and Marrow Transplantation and Cellular Therapy, Department of Medicine, Stanford University, Stanford, CA
Anna Pavlova
Alejandro Villar-Prados
1Division of Blood and Marrow Transplantation and Cellular Therapy, Department of Medicine, Stanford University, Stanford, CA
Cameron Bader
1Stanford University School of Medicine, Department of Medicine, Division of Blood and Marrow Transplantation & Cellular Therapy, Stanford, United States
Bryan Xie
1Stanford Blood and Marrow Transplantation and Cellular Therapy Division, Stanford School of Medicine, Stanford University, Stanford, CA
Lori Muffly
1Division of Blood and Marrow Transplantation & Cellular Therapy, Stanford University, Stanford, CA
Paige Kim
Princess Margaret Cancer Center
Katherine Sutherland
6Stanford University School of Medicine, Palo Alto, United States
Sushma Bharadwaj
2Stanford University School of Medicine, Medicine, Division of Blood and Marrow Transplantation & Cellular Therapy, Stanford, United States
Saurabh Dahiya
Matthew Frank
2Stanford University School of Medicine, Medicine, Division of Blood and Marrow Transplantation & Cellular Therapy, Stanford, United States
Sally Arai
Laura Johnston
2Stanford University School of Medicine, Medicine, Division of Blood and Marrow Transplantation & Cellular Therapy, Stanford, United States
David Miklos
Andrew Rezvani
21Stanford University School of Medicine, Stanford, United States
Parveen Shiraz
1Division of Blood and Marrow Transplantation & Cellular Therapy, Stanford University, Stanford, CA
Surbhi Sidana
Stanford University School of Medicine, Palo Alto, CA
Judy Shizuru
1Stanford Blood and Marrow Transplantation and Cellular Therapy Division, Stanford School of Medicine, Stanford University, Stanford, CA
Wen-Kai Weng
10Department of Medicine, Stanford University, Stanford, CA
Vaibhav Agrawal
1City of Hope, Duarte, United States
Amy Putnam
3Orca Bio, Menlo Park, CA
Nathaniel Fernhoff
3Orca Bio, Menlo Park, CA
John Tamarisis
5Department of Biomedical Data Sciences, Stanford University, Stanford, CA
Ying Lu
Rahul D. Pawar
6Division of Immunology and Rheumatology, Stanford University, Stanford, CA
J. Scott McClellan
6Orca Bio, Menlo Park, United States
Robert Lowsky
2Stanford University School of Medicine, Medicine, Division of Blood and Marrow Transplantation & Cellular Therapy, Stanford, United States
Robert S. Negrin
Stanford University Medical Center, Stanford, California, United States