A single dose of a CD137 antibody–drug conjugate protects rhesus macaque allogeneic HCT recipients against acute GVHD
Abstract
Abstract Rapid CD137 upregulation on alloreactive T cells upon allogeneic stimulation suggests that their selective elimination could prevent acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation (HCT). Here, we developed a novel aGVHD prophylactic regimen consisting of a single dose of an anti-CD137 antibody–drug conjugate (CD137-ADC) administered on the day of transplant without additional immunosuppression. The CD137-ADC depleted both human and nonhuman primate (NHP) activated T cells and proved highly effective in preventing xenogeneic aGVHD in mice receiving human peripheral blood mononuclear cells, as well as in NHP undergoing major histocompatibility complex (MHC)-haploidentical HCT. Flow cytometry analysis of NHP T cells indicated specific depletion of activated PD-1+ CD4 and CD8 T cells, while sparing naïve and PD-1−OX40+ memory T-cell subsets during the first week after HCT. CD137-ADC–treated NHP recipients demonstrated robust hematopoietic and immune reconstitution. Hallmarks of T-cell recovery after CD137-ADC, which were associated with long-term aGVHD-free survival, included reconstitution of CD4 memory T cells expressing TRAIL, terminally differentiated CD8 T cells expressing CX3CR1, and CD4 FoxP3+ regulatory T cells, cell types not expected to be involved in aGVHD pathogenesis. CD137-ADC–treated recipients demonstrated a higher risk of reactivation of rhesus lymphocryptovirus (the rhesus macaque Epstein-Barr virus analog), which was associated with reconstitution of follicular helper T cells, interferon signaling–associated memory, and γδT-cell subsets. This reactivation was controllable with rituximab administration. These results document effective depletion of alloreactive T cells and prevention of aGVHD after a single dose of CD137-ADC, suggesting that clinical translation should be carefully explored.
Article Details
Authors (25)
Ulrike Gerdemann
1Boston Children's Hospital / Dana-Farber Cancer Institute, Hematology/Oncology, Boston, United States
Kyle Kimler
4Cell Discovery Network of Boston Children's Hospital, Boston Children’s Hospital, Boston, MA
Matthew R. Warren
1Division of Pediatric Hematology-Oncology, Boston Children’s Hospital, Boston, MA
Connor McGuckin
1Division of Pediatric Hematology-Oncology, Boston Children’s Hospital, Boston, MA
Ryan A. Fleming
1Division of Pediatric Hematology-Oncology, Boston Children’s Hospital, Boston, MA
Matthew R. D’Ambra
6Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Boston, MA
Alal Eran
1Division of Pediatric Hematology-Oncology, Boston Children’s Hospital, Boston, MA
Alexandre Albanese
1Boston Children's Hospital, Department of Pediatrics, Boston, United States
Edward Chen
Marlana Winschel
2Boston Children's Hospital, Division of Hematology/Oncology, Boston, United States
Lorenzo Cagnin
1Boston Children's Hospital, Department of Pediatrics, Boston, United States
Jennifer Lane
1Boston Children's Hospital / Dana-Farber Cancer Institute, Hematology/Oncology, Boston, United States
Lev Gorfinkel
1Boston Children's Hospital, Department of Pediatrics, Boston, United States
Bartley Adams
7Duke Transplant Center, Department of Surgery, Duke University Medical Center, Durham, NC
Jean Kwun
7Duke Transplant Center, Department of Surgery, Duke University Medical Center, Durham, NC
Leanne Lanieri
8Magenta Therapeutics, Cambridge, MA
Megan Hoban
1Orna Therapeutics, Watertown, United States
Tahirih L. Lamothe
8Magenta Therapeutics, Cambridge, MA
Sharon Hyzy
3Vor Bio, Cambridge, United States
Lisa M. Olson
8Magenta Therapeutics, Cambridge, MA
Angela Panoskaltsis-Mortari
Susan E. Prockop
1Division of Pediatric Hematology-Oncology, Boston Children’s Hospital, Boston, MA
Bruce R. Blazar
Department of Pediatrics, Division of Blood & Marrow Transplant & Cellular Therapy, University of Minnesota
Leslie S. Kean
Dana–Farber Cancer Institute–Boston Children’s Hospital, Boston
Victor Tkachev
5Massachusetts General Hospital, Charlestown, United States