Stefanie Sarantopoulos

Positions:

Associate Professor of Medicine

Medicine, Hematologic Malignancies and Cellular Therapy
School of Medicine

Associate Professor of Immunology

Immunology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

M.D. 1998

Boston University

Ph.D. 1998

Boston University School of Medicine

Intern, Internal Medicine

Boston University School of Medicine

Resident, Internal Medicine

Boston University School of Medicine

Chief Resident, Internal Medicine

Boston University School of Medicine

Fellowship, Hematology/ Oncology

Dana-Farber Cancer Institute

Grants:

BAFF Pathology: Novel Therapeutic Targets in Chronic Graft versus Host Disease

Administered By
Medicine, Hematologic Malignancies and Cellular Therapy
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Breaking B-Cell Tolerance to Produce Antibodies that Eradicate Leukemias and Lymphomas

Administered By
Medicine, Hematologic Malignancies and Cellular Therapy
Awarded By
Department of Defense
Role
Principal Investigator
Start Date
End Date

The Notch2-BCR Axis: Targeting Drivers of B cell Fate in Chronic GVHD

Administered By
Medicine, Hematologic Malignancies and Cellular Therapy
Awarded By
Leukemia & Lymphoma Society
Role
Principal Investigator
Start Date
End Date

Understanding Aberrant TLR7 Signaling in B Cells from Patients with Chronic GVHD

Administered By
Medicine, Hematologic Malignancies and Cellular Therapy
Awarded By
American Society for Blood and Marrow Transplantation
Role
Principal Investigator
Start Date
End Date

A Phase II of Entospletinib, a SYK Inhibitor, First line cGVHD patients

Administered By
Duke Cancer Institute
Awarded By
Gilead Sciences, Inc.
Role
Principal Investigator
Start Date
End Date

Publications:

Phase I dose escalation study of naive T-cell depleted donor lymphocyte infusion following allogeneic stem cell transplantation.

Prophylactic donor lymphocyte infusions (DLI) are used to augment post-transplant immune recovery to reduce both infectious complications and disease recurrence. Preclinical studies implicate the naive T-cell subset as the primary driver of graft-versus-host disease (GvHD). In this phase I dose escalation study, we assessed the safety of a DLI that was depleted of CD45RA+ naive T cells. Sixteen adult patients received a prophylactic DLI at a median of 113 days (range 76-280 days) following an HLA-identical, non-myeloablative allogeneic hematopoietic stem cell transplantation. Three patients each received the naive T-cell depleted DLI with a CD3+ dose of 1 × 105/kg, 1 × 106/kg, and 5 × 106/kg. The maximum dose of 1 × 107/kg was expanded to 7 patients. No dose-limiting grade III/IV acute GvHD or adverse events attributable to the DLI were observed at any dose level. One patient developed grade 2 acute GvHD of skin and upper intestines, and another developed moderate chronic GvHD of the lungs following the DLI. With a median follow-up of 2.8 years, 2-year progression-free and overall survival is 50.0% and 68.8%, respectively. In conclusion, these data suggest that a DLI that has been depleted of CD45RA+ naive T cells is feasible and carries a low risk of acute or chronic GvHD.
Authors
Maung, KK; Chen, BJ; Barak, I; Li, Z; Rizzieri, DA; Gasparetto, C; Sullivan, KM; Long, GD; Engemann, AM; Waters-Pick, B; Nichols, KR; Lopez, R; Kang, Y; Sarantopoulos, S; Sung, AD; Chao, NJ; Horwitz, ME
MLA Citation
Maung, Ko K., et al. “Phase I dose escalation study of naive T-cell depleted donor lymphocyte infusion following allogeneic stem cell transplantation.Bone Marrow Transplant, July 2020. Pubmed, doi:10.1038/s41409-020-0991-5.
URI
https://scholars.duke.edu/individual/pub1450672
PMID
32624583
Source
pubmed
Published In
Bone Marrow Transplant
Published Date
DOI
10.1038/s41409-020-0991-5

Allogeneic HSCT for autoimmune disease: a shared decision.

MLA Citation
Sullivan, Keith M., and Stefanie Sarantopoulos. “Allogeneic HSCT for autoimmune disease: a shared decision.Nat Rev Rheumatol, vol. 15, no. 12, Dec. 2019, pp. 701–02. Pubmed, doi:10.1038/s41584-019-0306-7.
URI
https://scholars.duke.edu/individual/pub1412070
PMID
31530942
Source
pubmed
Published In
Nat Rev Rheumatol
Volume
15
Published Date
Start Page
701
End Page
702
DOI
10.1038/s41584-019-0306-7

Notch signaling mediated by Delta-like ligands 1 and 4 controls the pathogenesis of chronic GVHD in mice.

Chronic graft-versus-host disease (cGVHD) is a major complication of allogeneic hematopoietic cell transplantation (allo-HCT) and remains an area of unmet clinical need with few treatment options available. Notch blockade prevents acute GVHD in multiple mouse models, but the impact of Notch signaling on cGVHD remains unknown. Using genetic and antibody-mediated strategies of Notch inhibition, we investigated the role of Notch signaling in complementary mouse cGVHD models that mimic several aspects of human cGVHD in search of candidate therapeutics. In the B10.D2→BALB/c model of sclerodermatous cGVHD, Delta-like ligand 4 (Dll4)-driven Notch signaling was essential for disease development. Antibody-mediated Dll4 inhibition conferred maximum benefits when pursued early in a preventative fashion, with anti-Dll1 enhancing early protection. Notch-deficient alloantigen-specific T cells showed no early defects in proliferation or helper polarization in vivo but subsequently exhibited markedly decreased cytokine secretion and enhanced accumulation of FoxP3+ regulatory T cells. In the B6→B10.BR major histocompatibility complex-mismatched model with multi-organ system cGVHD and prominent bronchiolitis obliterans (BO), but not skin manifestations, absence of Notch signaling in T cells provided long-lasting disease protection that was replicated by systemic targeting of Dll1, Dll4, or both Notch ligands, even during established disease. Notch inhibition decreased target organ damage and germinal center formation. Moreover, decreased BO-cGVHD was observed upon inactivation of Notch1 and/or Notch2 in T cells. Systemic targeting of Notch2 alone was safe and conferred therapeutic benefits. Altogether, Notch ligands and receptors regulate key pathogenic steps in cGVHD and emerge as novel druggable targets to prevent or treat different forms of cGVHD.
Authors
Radojcic, V; Paz, K; Chung, J; Du, J; Perkey, ET; Flynn, R; Ivcevic, S; Zaiken, M; Friedman, A; Yan, M; Pletneva, MA; Sarantopoulos, S; Siebel, CW; Blazar, BR; Maillard, I
MLA Citation
Radojcic, Vedran, et al. “Notch signaling mediated by Delta-like ligands 1 and 4 controls the pathogenesis of chronic GVHD in mice.Blood, vol. 132, no. 20, Nov. 2018, pp. 2188–200. Pubmed, doi:10.1182/blood-2018-03-841155.
URI
https://scholars.duke.edu/individual/pub1347002
PMID
30181175
Source
pubmed
Published In
Blood
Volume
132
Published Date
Start Page
2188
End Page
2200
DOI
10.1182/blood-2018-03-841155

The Biology of Chronic Graft-versus-Host Disease: A Task Force Report from the National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease.

Chronic graft-versus-host disease (GVHD) is the leading cause of late, nonrelapse mortality and disability in allogeneic hematopoietic cell transplantation recipients and a major obstacle to improving outcomes. The biology of chronic GVHD remains enigmatic, but understanding the underpinnings of the immunologic mechanisms responsible for the initiation and progression of disease is fundamental to developing effective prevention and treatment strategies. The goals of this task force review are as follows: This document is intended as a review of our understanding of chronic GVHD biology and therapies resulting from preclinical studies, and as a platform for developing innovative clinical strategies to prevent and treat chronic GVHD.
Authors
Cooke, KR; Luznik, L; Sarantopoulos, S; Hakim, FT; Jagasia, M; Fowler, DH; van den Brink, MRM; Hansen, JA; Parkman, R; Miklos, DB; Martin, PJ; Paczesny, S; Vogelsang, G; Pavletic, S; Ritz, J; Schultz, KR; Blazar, BR
MLA Citation
Cooke, Kenneth R., et al. “The Biology of Chronic Graft-versus-Host Disease: A Task Force Report from the National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease.Biol Blood Marrow Transplant, vol. 23, no. 2, Feb. 2017, pp. 211–34. Pubmed, doi:10.1016/j.bbmt.2016.09.023.
URI
https://scholars.duke.edu/individual/pub1147489
PMID
27713092
Source
pubmed
Published In
Biol Blood Marrow Transplant
Volume
23
Published Date
Start Page
211
End Page
234
DOI
10.1016/j.bbmt.2016.09.023

Targeting Syk-activated B cells in murine and human chronic graft-versus-host disease.

Novel therapies for chronic graft-versus-host disease (cGVHD) are needed. Aberrant B-cell activation has been demonstrated in mice and humans with cGVHD. Having previously found that human cGVHD B cells are activated and primed for survival, we sought to further evaluate the role of the spleen tyrosine kinase (Syk) in cGVHD in multiple murine models and human peripheral blood cells. In a murine model of multiorgan system, nonsclerodermatous disease with bronchiolitis obliterans where cGVHD is dependent on antibody and germinal center (GC) B cells, we found that activation of Syk was necessary in donor B cells, but not T cells, for disease progression. Bone marrow-specific Syk deletion in vivo was effective in treating established cGVHD, as was a small-molecule inhibitor of Syk, fostamatinib, which normalized GC formation and decreased activated CD80/86(+) dendritic cells. In multiple distinct models of sclerodermatous cGVHD, clinical and pathological disease manifestations were not eliminated when mice were therapeutically treated with fostamatinib, though both clinical and immunologic effects could be observed in one of these scleroderma models. We further demonstrated that Syk inhibition was effective at inducing apoptosis of human cGVHD B cells. Together, these data demonstrate a therapeutic potential of targeting B-cell Syk signaling in cGVHD.
Authors
Flynn, R; Allen, JL; Luznik, L; MacDonald, KP; Paz, K; Alexander, KA; Vulic, A; Du, J; Panoskaltsis-Mortari, A; Taylor, PA; Poe, JC; Serody, JS; Murphy, WJ; Hill, GR; Maillard, I; Koreth, J; Cutler, CS; Soiffer, RJ; Antin, JH; Ritz, J; Chao, NJ; Clynes, RA; Sarantopoulos, S; Blazar, BR
MLA Citation
Flynn, Ryan, et al. “Targeting Syk-activated B cells in murine and human chronic graft-versus-host disease.Blood, vol. 125, no. 26, June 2015, pp. 4085–94. Pubmed, doi:10.1182/blood-2014-08-595470.
URI
https://scholars.duke.edu/individual/pub1061937
PMID
25852057
Source
pubmed
Published In
Blood
Volume
125
Published Date
Start Page
4085
End Page
4094
DOI
10.1182/blood-2014-08-595470