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
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
Role
Principal Investigator
Start Date
End Date

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

Administered By
Duke Cancer Institute
Role
Principal Investigator
Start Date
End Date

Publications:

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

Design and Patient Characteristics of the Chronic Graft-versus-Host Disease Response Measures Validation Study.

In 2014, the National Institutes of Health sponsored the second Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease (GVHD). The purpose was to update recommendations about key elements of chronic GVHD research, including definitions for diagnosis, severity scoring, and response measures, based on empirical data published since the first 2005 Consensus Conference. The most significant modifications were to the response assessments, based on studies demonstrating difficulty with the first consensus definitions. The Response Measures Validation Study is a multicenter, prospective cohort study of patients who are starting initial or subsequent treatments for chronic GVHD. The aim of the study is to evaluate the performance of the 2014 response measures and determine whether any other combination of assessments is superior. Clinical data, clinician assessments, patient-reported outcomes, and research samples are collected at enrollment and 3, 6, and 18 months later, and whenever another chronic GVHD systemic treatment is added. The target enrollment of 368 evaluable patients from 12 transplantation centers has been reached. This report describes the rationale, design, and methods of the Chronic GVHD Response Measures Validation Study, and invites other investigators to collaborate with the Consortium to analyze data or specimens.
Authors
Chronic GVHD Consortium,
MLA Citation
Chronic GVHD Consortium, Pietro. “Design and Patient Characteristics of the Chronic Graft-versus-Host Disease Response Measures Validation Study..” Biol Blood Marrow Transplant, vol. 24, no. 8, Aug. 2018, pp. 1727–32. Pubmed, doi:10.1016/j.bbmt.2018.02.010.
URI
https://scholars.duke.edu/individual/pub1311672
PMID
29476954
Source
pubmed
Published In
Biol Blood Marrow Transplant
Volume
24
Published Date
Start Page
1727
End Page
1732
DOI
10.1016/j.bbmt.2018.02.010

All-Trans Retinoic Acid (ATRA) Targets IRF4 Deficient, NOTCH2-Activated B Cells from Chronic Gvhd Patients

<jats:title>Abstract</jats:title> <jats:p>Allogeneic hematopoietic stem cell transplantation (HCT)-related immune pathology severely limits patient (Pt) survival, largely due to infections. Chronic graft versus host disease (cGVHD) Pts are particularly immune incompetent with impaired memory B cell responses. Paradoxically, cGVHD Pts are hypogammaglobulinemic and yet are variably immune tolerant with potentially pathogenic alloantibodies frequently produced. B cells with marginal zone (MZ)-like properties are expanded in cGVHD Pts with high BAFF/B-cell ratios (rev. Sarantopoulos, Blood 2015), similar to findings in BAFF-overexpressing mice. We previously found that the increased BCR responsiveness of cGVHD B cells depended on NOTCH2 signaling, since a specific monoclonal antibody (Genentech) blocked hyperactivation (ASH 2015 oral abstract: Blood. 2015. 126:145). Our current objective is to define the molecular defects underlying this aberrant NOTCH2-BCR axis.</jats:p> <jats:p>Increased NOTCH2 expression/activity is found in mice genetically deficient in the transcription factor IRF4 (J. Exp. Med. 2013. 210:2887-2902). Likewise, IRF4 levels are subnormal in unstimulated B cells from active cGVHD Pts relative to healthy donors (Blood. 2014. 123: 2108-15). Thus, we hypothesized that a B cell-intrinsic IRF4 deficiency contributes to the NOTCH2-BCR axis in cGVHD. We studied multi-center (Duke Univ., NCI-NIH, Dana Farber Cancer Inst.) de-identified clinical samples from 38 Pts with or without NIH diagnostic criteria of cGVHD who were &gt;12 months post-HCT and not receiving high dose steroids. We employed our in vitro culture system utilizing NOTCH ligand-expressing feeder cells and measured proliferative responses (Ki-67% by flow cytometry) to surrogate Ag. First, adding to our previous findings, B cells from active cGVHD Pts (n=8) proliferated robustly to minimal BCR ligation when NOTCH was activated compared to B cells from Pts without cGVHD (n=7) (38.1% vs 15.3%, P =0.006). To test our new hypothesis, IRF4 levels were determined by quantitative PCR analysis in B cells isolated from HCT Pts with active cGVHD and with no cGVHD stimulated ex vivo for 24 hours (h) with a limiting amount of surrogate Ag (anti-IgM). BCR-engaged B cells from active cGVHD Pts (Figure 1A, open bars) maintained significantly lower IRF4 levels compared to B cells from Pts with no cGVHD (Figure 1A, filled bars; n=4 in each group, P =0.01 in a two-sided t-test).</jats:p> <jats:p>Importantly, this IRF4 deficiency may be correctable therapeutically in cGVHD Pts, since the ex vivo treatment of human B cells with all-trans retinoic acid (ATRA) increases IRF4 expression (J. Immunol. 2015. 195:2601-11), and ATRA has demonstrated efficacy in a mouse model of cGVHD (Blood. 2012. 119:285-95). When ATRA (100 nM) was added to cultures of surrogate Ag-stimulated B cells (Figure 1A, right), IRF4 levels increased significantly in both active cGVHD B cells (n = 4, P &lt;0.05 in a two-sided t-test) and no cGVHD B cells (n = 4, P &lt; 0.01 in a two-sided t-test). Nevertheless, even with ATRA treatment the level of IRF4 remained significantly less in B cells from active cGVHD Pts compared to no cGVHD Pts (P &lt;0.01 in a two-sided t-test). To determine whether IRF4 expression could also be enhanced when the NOTCH2-BCR axis is engaged, as could occur in vivo in Pts, we subjected active cGVHD B cells to NOTCH ligand-expressing feeder cells. When assessed by intracellular staining and flow cytometry, IRF4 protein increased following 24h of ATRA treatment relative to vehicle alone, either in the presence or absence of surrogate Ag (Figure 1B and data not shown, one of 6 representative Pts assessed displayed). Strikingly, ATRA treatment completely abolished NOTCH2-BCR hyper-responsiveness of active cGVHD B cells, as evaluated by Ki-67 staining after 72h using flow cytometry (Figure 1C, n=6 in each group, P &lt;0.01 in a two-sided t-test).</jats:p> <jats:p>In summary, we have revealed skewing of a key B cell maturation pathway in active cGVHD. Our data suggest that an intrinsic defect in IRF4 expression dictates heightened NOTCH2-BCR responsiveness. This defect may be corrected by retinoids or similar agents that promote IRF4 expression. Thus, we have identified a candidate molecular target for blocking aberrant B cell activation and potentially inducing functional B cell development.</jats:p> <jats:p>This work was supported by a Translational Research Program grant from the Leukemia &amp; Lymphoma Society and a National Institutes of Health grant, NIH (NHLBI) R01 HL 129061-01.</jats:p> <jats:p>Figure 1. Figure 1.</jats:p> <jats:sec> <jats:title>Disclosures</jats:title> <jats:p>Ritz: Kiadis: Membership on an entity's Board of Directors or advisory committees. Siebel:Genentech Inc.: Employment, Equity Ownership.</jats:p> </jats:sec>
Authors
Poe, JC; Jia, W; Su, H; Li, Z; Hakim, FT; Pavletic, SZ; Rose, JJ; Rizzieri, DA; Yang, Y; Chen, BJ; Anand, S; Ritz, J; Siebel, CW; Chao, NJ; Maillard, I; Sarantopoulos, S
MLA Citation
Poe, Jonathan C., et al. “All-Trans Retinoic Acid (ATRA) Targets IRF4 Deficient, NOTCH2-Activated B Cells from Chronic Gvhd Patients.” Blood, vol. 128, no. 22, American Society of Hematology, 2016, pp. 669–669. Crossref, doi:10.1182/blood.v128.22.669.669.
URI
https://scholars.duke.edu/individual/pub1346460
Source
crossref
Published In
Blood
Volume
128
Published Date
Start Page
669
End Page
669
DOI
10.1182/blood.v128.22.669.669

Delayed Reconstitution of Bone Marrow B Cell Precursors After Allogeneic Stem Cell Transplantation Is Associated With Chronic Graft Versus Host Disease (cGVHD)

Authors
Fedoriw, Y; Cichon, L; Dokouhaki, P; Mathews, S; Sharf, A; Sarantopoulos, S
MLA Citation
URI
https://scholars.duke.edu/individual/pub1064834
Source
wos
Published In
Modern Pathology : an Official Journal of the United States and Canadian Academy of Pathology, Inc
Volume
28
Published Date
Start Page
344A
End Page
344A

Further examination of BAFF SNPs in cGVHD.

Authors
Fore, M; Jagasia, M; Sarantopoulos, S; Richards, KL
MLA Citation
Fore, Matthew, et al. “Further examination of BAFF SNPs in cGVHD..” Blood, vol. 120, no. 3, July 2012, pp. 700–01. Pubmed, doi:10.1182/blood-2012-05-428409.
URI
https://scholars.duke.edu/individual/pub1115020
PMID
22822003
Source
pubmed
Published In
Blood
Volume
120
Published Date
Start Page
700
End Page
701
DOI
10.1182/blood-2012-05-428409