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Sarantopoulos, Stefanie

Positions:

Associate Professor of Medicine

Medicine, Cellular Therapy
School of Medicine

Assistant Professor of Immunology

Immunology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

M.D. 1998

M.D. — Boston University

Ph.D. 1998

Ph.D. — Boston University School of Medicine

Grants:

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

Administered By
Duke Cancer Institute
AwardedBy
Gilead Sciences, Inc.
Role
Principal Investigator
Start Date
May 31, 2016
End Date
May 30, 2021

Pathological B Cells: Novel Strategies to Prevent and Treat Chronic GVHD

Administered By
Medicine, Cellular Therapy
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
August 15, 2015
End Date
June 30, 2020

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

Administered By
Medicine, Cellular Therapy
AwardedBy
Leukemia & Lymphoma Society
Role
Principal Investigator
Start Date
October 01, 2015
End Date
September 30, 2018

The Effects of Syk Blockade with GS-9973 on Immunity in a Murine Model of GVHD

Administered By
Medicine, Cellular Therapy
AwardedBy
Gilead Sciences, Inc.
Role
Principal Investigator
Start Date
April 01, 2016
End Date
March 31, 2018

BAFF-Driven Targeted Immunotherapy for Patients with Leukemia

Administered By
Medicine, Cellular Therapy
AwardedBy
Department of Defense
Role
Principal Investigator
Start Date
August 01, 2011
End Date
November 30, 2015

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

Administered By
Medicine, Cellular Therapy
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
July 12, 2011
End Date
June 30, 2015
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Publications:

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, 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, and Blazar, BR. "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." Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 23.2 (February 2017): 211-234.
PMID
27713092
Source
epmc
Published In
Biology of Blood and Marrow Transplantation
Volume
23
Issue
2
Publish Date
2017
Start Page
211
End Page
234
DOI
10.1016/j.bbmt.2016.09.023

Outcomes of Maintenance Therapy with Bortezomib after Autologous Stem Cell Transplantation for Patients with Multiple Myeloma.

Comprehensive recommendations for maintenance therapy after autologous stem cell transplantation (ASCT) for patients with multiple myeloma (MM) have yet to be defined. Bortezomib has been utilized as maintenance therapy after ASCT, but data attesting to the safety and efficacy of this agent compared with lenalidomide in the post-ASCT setting are limited. Therefore, we retrospectively analyzed the outcomes of 102 patients with MM who received maintenance therapy with bortezomib after ASCT at Duke University's adult bone marrow transplant clinic between 2005 and 2015. Maintenance with bortezomib was initiated between 60 and 90 days after ASCT as a single agent 1.3 mg/m2 once every 2 weeks (n = 92) or in combination with lenalidomide (10 mg/day) (n = 10). The median age at ASCT was 64 (range, 31 to 78). Of the 99 patients with molecular data available, 42% had high-risk cytogenetics (including d17p, t(4;14), +1q, and t(14;16) by fluorescein in situ hybridization). Overall, 46% of patients experienced side effects from maintenance therapy, with 31% of all patients experiencing peripheral neuropathy. In total, 2% of patients required discontinuation of bortezomib maintenance because of adverse events. No secondary malignancies were reported from the therapy. The median progression-free survival (PFS) for patients receiving maintenance therapy with bortezomib after ASCT was 36.5 months (95% confidence interval [CI], 21.3 to not available) and median overall survival was 72.7 months (95% CI, 63.9 to not available). The PFS of patients with high-risk cytogenetics was not statistically significantly different from those with standard-risk cytogenetics, suggesting that maintenance with bortezomib may help overcome the impact of high-risk cytogenetics on early progression. These results indicate that maintenance therapy with bortezomib represents a safe, well-tolerated, and efficacious option for patients with high-risk cytogenetics, renal insufficiency, an inability to tolerate lenalidomide, or a previous history of another cancer.

Authors
Sivaraj, D; Green, MM; Li, Z; Sung, AD; Sarantopoulos, S; Kang, Y; Long, GD; Horwitz, ME; Lopez, RD; Sullivan, KM; Rizzieri, DA; Chao, NJ; Gasparetto, C
MLA Citation
Sivaraj, D, Green, MM, Li, Z, Sung, AD, Sarantopoulos, S, Kang, Y, Long, GD, Horwitz, ME, Lopez, RD, Sullivan, KM, Rizzieri, DA, Chao, NJ, and Gasparetto, C. "Outcomes of Maintenance Therapy with Bortezomib after Autologous Stem Cell Transplantation for Patients with Multiple Myeloma." Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 23.2 (February 2017): 262-268.
PMID
27856369
Source
epmc
Published In
Biology of Blood and Marrow Transplantation
Volume
23
Issue
2
Publish Date
2017
Start Page
262
End Page
268
DOI
10.1016/j.bbmt.2016.11.010

National Institutes of Health Hematopoietic Cell Transplantation Late Effects Initiative: The Immune Dysregulation and Pathobiology Working Group Report.

Immune reconstitution after hematopoietic stem cell transplantation (HCT) beyond 1 year is not completely understood. Many transplant recipients who are free of graft-versus-host disease (GVHD) and not receiving any immunosuppression more than 1 year after transplantation seem to be able to mount appropriate immune responses to common pathogens and respond adequately to immunizations. However, 2 large registry studies over the last 2 decades seem to indicate that infection is a significant cause of late mortality in some patients, even in the absence of concomitant GVHD. Research on this topic is particularly challenging for several reasons. First, there are not enough long-term follow-up clinics able to measure even basic immune parameters late after HCT. Second, the correlation between laboratory measurements of immune function and infections is not well known. Third, accurate documentation of infectious episodes is notoriously difficult. Finally, it is unclear what measures can be implemented to improve the immune response in a clinically relevant way. A combination of long-term multicenter prospective studies that collect detailed infectious data and store samples as well as a national or multinational registry of clinically significant infections (eg, vaccine-preventable severe infections, opportunistic infections) could begin to address our knowledge gaps. Obtaining samples for laboratory evaluation of the immune system should be both calendar and eventdriven. Attention to detail and standardization of practices regarding prophylaxis, diagnosis, and definitions of infections would be of paramount importance to obtain clean reliable data. Laboratory studies should specifically address the neogenesis, maturation, and exhaustion of the adaptive immune system and, in particular, how these are influenced by persistent alloreactivity, inflammation, and viral infection. Ideally, some of these long-term prospective studies would collect information on long-term changes in the gut microbiome and their influence on immunity. Regarding enhancement of immune function, prospective measurement of the response to vaccines late after HCT in a variety of clinical settings should be undertaken to better understand the benefits as well as the limitations of immunizations. The role of intravenous immunoglobulin is still not well defined, and studies to address it should be encouraged.

Authors
Gea-Banacloche, J; Komanduri, KV; Carpenter, P; Paczesny, S; Sarantopoulos, S; Young, J-A; El Kassar, N; Le, RQ; Schultz, KR; Griffith, LM; Savani, BN; Wingard, JR
MLA Citation
Gea-Banacloche, J, Komanduri, KV, Carpenter, P, Paczesny, S, Sarantopoulos, S, Young, J-A, El Kassar, N, Le, RQ, Schultz, KR, Griffith, LM, Savani, BN, and Wingard, JR. "National Institutes of Health Hematopoietic Cell Transplantation Late Effects Initiative: The Immune Dysregulation and Pathobiology Working Group Report." Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation (October 14, 2016).
PMID
27751936
Source
epmc
Published In
Biology of Blood and Marrow Transplantation
Publish Date
2016
DOI
10.1016/j.bbmt.2016.10.001

Review: Hematopoietic Stem Cell Transplantation for Scleroderma: Effective Immunomodulatory Therapy for Patients With Pulmonary Involvement.

Authors
Sullivan, KM; Shah, A; Sarantopoulos, S; Furst, DE
MLA Citation
Sullivan, KM, Shah, A, Sarantopoulos, S, and Furst, DE. "Review: Hematopoietic Stem Cell Transplantation for Scleroderma: Effective Immunomodulatory Therapy for Patients With Pulmonary Involvement." Arthritis & rheumatology (Hoboken, N.J.) 68.10 (October 2016): 2361-2371. (Review)
Website
http://hdl.handle.net/10161/12558
PMID
27213276
Source
epmc
Published In
Arthritis and Rheumatology
Volume
68
Issue
10
Publish Date
2016
Start Page
2361
End Page
2371
DOI
10.1002/art.39748

Plerixafor (a CXCR4 antagonist) following myeloablative allogeneic hematopoietic stem cell transplantation enhances hematopoietic recovery.

The binding of CXCR4 with its ligand (stromal-derived factor-1) maintains hematopoietic stem/progenitor cells (HSPCs) in a quiescent state. We hypothesized that blocking CXCR4/SDF-1 interaction after hematopoietic stem cell transplantation (HSCT) promotes hematopoiesis by inducing HSC proliferation.We conducted a phase I/II trial of plerixafor on hematopoietic cell recovery following myeloablative allogeneic HSCT. Patients with hematologic malignancies receiving myeloablative conditioning were enrolled. Plerixafor 240 μg/kg was administered subcutaneously every other day beginning day +2 until day +21 or until neutrophil recovery. The primary efficacy endpoints of the study were time to absolute neutrophil count >500/μl and platelet count >20,000/μl. The cumulative incidence of neutrophil and platelet engraftment of the study cohort was compared to that of a cohort of 95 allogeneic peripheral blood stem cell transplant recipients treated during the same period of time and who received similar conditioning and graft-versus-host disease prophylaxis.Thirty patients received plerixafor following peripheral blood stem cell (n = 28) (PBSC) or bone marrow (n = 2) transplantation. Adverse events attributable to plerixafor were mild and indistinguishable from effects of conditioning. The kinetics of neutrophil and platelet engraftment, as demonstrated by cumulative incidence, from the 28 study subjects receiving PBSC showed faster neutrophil (p = 0.04) and platelet recovery >20 K (p = 0.04) compared to the controls.Our study demonstrated that plerixafor can be given safely following myeloablative HSCT. It provides proof of principle that blocking CXCR4 after HSCT enhances hematopoietic recovery. Larger, confirmatory studies in other settings are warranted.ClinicalTrials.gov NCT01280955.

Authors
Green, MMB; Chao, N; Chhabra, S; Corbet, K; Gasparetto, C; Horwitz, A; Li, Z; Venkata, JK; Long, G; Mims, A; Rizzieri, D; Sarantopoulos, S; Stuart, R; Sung, AD; Sullivan, KM; Costa, L; Horwitz, M; Kang, Y
MLA Citation
Green, MMB, Chao, N, Chhabra, S, Corbet, K, Gasparetto, C, Horwitz, A, Li, Z, Venkata, JK, Long, G, Mims, A, Rizzieri, D, Sarantopoulos, S, Stuart, R, Sung, AD, Sullivan, KM, Costa, L, Horwitz, M, and Kang, Y. "Plerixafor (a CXCR4 antagonist) following myeloablative allogeneic hematopoietic stem cell transplantation enhances hematopoietic recovery." Journal of hematology & oncology 9.1 (August 17, 2016): 71-.
PMID
27535663
Source
epmc
Published In
Journal of Hematology and Oncology
Volume
9
Issue
1
Publish Date
2016
Start Page
71
DOI
10.1186/s13045-016-0301-2

Rad18 confers hematopoietic progenitor cell DNA damage tolerance independently of the Fanconi Anemia pathway in vivo.

In cultured cancer cells the E3 ubiquitin ligase Rad18 activates Trans-Lesion Synthesis (TLS) and the Fanconi Anemia (FA) pathway. However, physiological roles of Rad18 in DNA damage tolerance and carcinogenesis are unknown and were investigated here. Primary hematopoietic stem and progenitor cells (HSPC) co-expressed RAD18 and FANCD2 proteins, potentially consistent with a role for Rad18 in FA pathway function during hematopoiesis. However, hematopoietic defects typically associated with fanc-deficiency (decreased HSPC numbers, reduced engraftment potential of HSPC, and Mitomycin C (MMC) -sensitive hematopoiesis), were absent in Rad18(-/-) mice. Moreover, primary Rad18(-/-) mouse embryonic fibroblasts (MEF) retained robust Fancd2 mono-ubiquitination following MMC treatment. Therefore, Rad18 is dispensable for FA pathway activation in untransformed cells and the Rad18 and FA pathways are separable in hematopoietic cells. In contrast with responses to crosslinking agents, Rad18(-/-) HSPC were sensitive to in vivo treatment with the myelosuppressive agent 7,12 Dimethylbenz[a]anthracene (DMBA). Rad18-deficient fibroblasts aberrantly accumulated DNA damage markers after DMBA treatment. Moreover, in vivo DMBA treatment led to increased incidence of B cell malignancy in Rad18(-/-) mice. These results identify novel hematopoietic functions for Rad18 and provide the first demonstration that Rad18 confers DNA damage tolerance and tumor-suppression in a physiological setting.

Authors
Yang, Y; Poe, JC; Yang, L; Fedoriw, A; Desai, S; Magnuson, T; Li, Z; Fedoriw, Y; Araki, K; Gao, Y; Tateishi, S; Sarantopoulos, S; Vaziri, C
MLA Citation
Yang, Y, Poe, JC, Yang, L, Fedoriw, A, Desai, S, Magnuson, T, Li, Z, Fedoriw, Y, Araki, K, Gao, Y, Tateishi, S, Sarantopoulos, S, and Vaziri, C. "Rad18 confers hematopoietic progenitor cell DNA damage tolerance independently of the Fanconi Anemia pathway in vivo." Nucleic acids research 44.9 (May 2016): 4174-4188.
Website
http://hdl.handle.net/10161/12561
PMID
26883629
Source
epmc
Published In
Nucleic Acids Research
Volume
44
Issue
9
Publish Date
2016
Start Page
4174
End Page
4188
DOI
10.1093/nar/gkw072

Antibodies are back for thymic attack in cGVHD.

Authors
Sarantopoulos, S
MLA Citation
Sarantopoulos, S. "Antibodies are back for thymic attack in cGVHD." Blood 127.18 (May 2016): 2170-2171.
Website
http://hdl.handle.net/10161/12560
PMID
27151737
Source
epmc
Published In
Blood
Volume
127
Issue
18
Publish Date
2016
Start Page
2170
End Page
2171
DOI
10.1182/blood-2016-03-701706

Monitoring the kinetics of B-cell recovery following rituximab may guide the management of steroid-refractory chronic GvHD.

Authors
DeFilipp, Z; Purcell, M; Harris, WAC; Chandra, DJ; Gleason, C; Wrammert, J; Sarantopoulos, S; Waller, EK
MLA Citation
DeFilipp, Z, Purcell, M, Harris, WAC, Chandra, DJ, Gleason, C, Wrammert, J, Sarantopoulos, S, and Waller, EK. "Monitoring the kinetics of B-cell recovery following rituximab may guide the management of steroid-refractory chronic GvHD." Bone marrow transplantation 51.4 (April 2016): 607-609.
PMID
26642338
Source
epmc
Published In
Bone Marrow Transplantation
Volume
51
Issue
4
Publish Date
2016
Start Page
607
End Page
609
DOI
10.1038/bmt.2015.304

Transplantation of Ex vivo Expanded Umbilical Cord Blood (Nicord) Results in Decreased Infection Burden and Hospital Length of Stay in the First 100 Days

Authors
Anand, S; Thomas, S; Hyslop, T; Corbet, K; Gasparetto, C; Long, G; Morris, A; Rizzieri, D; Sarantopoulos, S; Sullivan, K; Sung, A; Chao, N; Horwitz, M
MLA Citation
Anand, S, Thomas, S, Hyslop, T, Corbet, K, Gasparetto, C, Long, G, Morris, A, Rizzieri, D, Sarantopoulos, S, Sullivan, K, Sung, A, Chao, N, and Horwitz, M. "Transplantation of Ex vivo Expanded Umbilical Cord Blood (Nicord) Results in Decreased Infection Burden and Hospital Length of Stay in the First 100 Days." March 2016.
Source
wos-lite
Published In
Bone Marrow Transplantation
Volume
51
Publish Date
2016
Start Page
S52
End Page
S53

A Randomized Phase II Crossover Study of Imatinib or Rituximab for Cutaneous Sclerosis after Hematopoietic Cell Transplantation.

Cutaneous sclerosis occurs in 20% of patients with chronic graft-versus-host disease (GVHD) and can compromise mobility and quality of life.We conducted a prospective, multicenter, randomized, two-arm phase II crossover trial of imatinib (200 mg daily) or rituximab (375 mg/m(2) i.v. weekly × 4 doses, repeatable after 3 months) for treatment of cutaneous sclerosis diagnosed within 18 months (NCT01309997). The primary endpoint was significant clinical response (SCR) at 6 months, defined as quantitative improvement in skin sclerosis or joint range of motion. Treatment success was defined as SCR at 6 months without crossover, recurrent malignancy or death. Secondary endpoints included changes of B-cell profiles in blood (BAFF levels and cellular subsets), patient-reported outcomes, and histopathology between responders and nonresponders with each therapy.SCR was observed in 9 of 35 [26%; 95% confidence interval (CI); 13%-43%] participants randomized to imatinib and 10 of 37 (27%; 95% CI, 14%-44%) randomized to rituximab. Six (17%; 95% CI, 7%-34%) patients in the imatinib arm and 5 (14%; 95% CI, 5%-29%) in the rituximab arm had treatment success. Higher percentages of activated B cells (CD27(+)) were seen at enrollment in rituximab-treated patients who had treatment success (P = 0.01), but not in imatinib-treated patients.These results support the need for more effective therapies for cutaneous sclerosis and suggest that activated B cells define a subgroup of patients with cutaneous sclerosis who are more likely to respond to rituximab.

Authors
Arai, S; Pidala, J; Pusic, I; Chai, X; Jaglowski, S; Khera, N; Palmer, J; Chen, GL; Jagasia, MH; Mayer, SA; Wood, WA; Green, M; Hyun, TS; Inamoto, Y; Storer, BE; Miklos, DB; Shulman, HM; Martin, PJ; Sarantopoulos, S; Lee, SJ; Flowers, MED
MLA Citation
Arai, S, Pidala, J, Pusic, I, Chai, X, Jaglowski, S, Khera, N, Palmer, J, Chen, GL, Jagasia, MH, Mayer, SA, Wood, WA, Green, M, Hyun, TS, Inamoto, Y, Storer, BE, Miklos, DB, Shulman, HM, Martin, PJ, Sarantopoulos, S, Lee, SJ, and Flowers, MED. "A Randomized Phase II Crossover Study of Imatinib or Rituximab for Cutaneous Sclerosis after Hematopoietic Cell Transplantation." Clinical cancer research : an official journal of the American Association for Cancer Research 22.2 (January 2016): 319-327.
Website
http://hdl.handle.net/10161/12562
PMID
26378033
Source
epmc
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
22
Issue
2
Publish Date
2016
Start Page
319
End Page
327
DOI
10.1158/1078-0432.ccr-15-1443

Targeting the Human Notch 2-BCR Axis: A Driver of B-Cell Hyper-Responsiveness in Active Chronic Graft-Versus Host Disease (cGVHD)

Authors
Poe, JC; Jia, W; Li, Z; Hakim, FT; Pavletic, SZ; Rose, JJ; Rizzieri, DA; Yang, Y; Chen, BJ; Green, M; Anand, S; Siebel, CW; Maillard, I; Chao, NJ; Sarantopoulos, S
MLA Citation
Poe, JC, Jia, W, Li, Z, Hakim, FT, Pavletic, SZ, Rose, JJ, Rizzieri, DA, Yang, Y, Chen, BJ, Green, M, Anand, S, Siebel, CW, Maillard, I, Chao, NJ, and Sarantopoulos, S. "Targeting the Human Notch 2-BCR Axis: A Driver of B-Cell Hyper-Responsiveness in Active Chronic Graft-Versus Host Disease (cGVHD)." December 3, 2015.
Source
wos-lite
Published In
Blood
Volume
126
Issue
23
Publish Date
2015

Reduced Intensity Continuous Infusion Busulfan for Allogeneic Hematopoietic Cell Transplant Patients with Hematologic Disorders Who Are Ineligible or Inappropriate for Treatment with a More Intensive Therapeutic Regimen: LCCC 0306

Authors
Friend, R; Xenakis, J; Serody, JS; Comeau, T; Gabriel, DA; Sarantopoulos, S; Coghill, J; Wood, WA; Sharf, A; Whitley, JS; Rao, K; Walko, CM; Ivanova, A; Shea, TC; Armistead, PM
MLA Citation
Friend, R, Xenakis, J, Serody, JS, Comeau, T, Gabriel, DA, Sarantopoulos, S, Coghill, J, Wood, WA, Sharf, A, Whitley, JS, Rao, K, Walko, CM, Ivanova, A, Shea, TC, and Armistead, PM. "Reduced Intensity Continuous Infusion Busulfan for Allogeneic Hematopoietic Cell Transplant Patients with Hematologic Disorders Who Are Ineligible or Inappropriate for Treatment with a More Intensive Therapeutic Regimen: LCCC 0306." December 3, 2015.
Source
wos-lite
Published In
Blood
Volume
126
Issue
23
Publish Date
2015

Phase I/II Trial of Dose-Escalated Busulfan Delivered by Prolonged Continuous Infusion in Allogeneic Transplant Patients.

Intensive chemotherapy or chemotherapy plus irradiation and allogeneic stem cell transplantation can be curative for patients with hematologic diseases. Reduced-intensity transplants can also achieve cure and result in less treatment-related mortality but higher relapse rates. Thus, optimizing the conditioning regimens used in allogeneic transplantation remains an important goal. We conducted a phase I/II trial to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of a continuous infusion of busulfan over 90 hours in conjunction with fludarabine followed by allogeneic related or unrelated donor transplant. Fifty-four patients with advanced hematologic malignancies were enrolled on this study. The MTD was identified as a 24-hour area under the curve (AUC) of approximately 7095 μM/min, which represents a 43% increase over the standard total daily AUC dose of 4800 μM/min given by intermittent schedules. DLTs at doses over 8000 μM/min were identified by a desquamative skin rash and mucositis. No dose-related increase in hepatic, pulmonary, or other organ toxicities were seen, whereas efficacy appeared to be improved at higher dose levels. Continuous-infusion busulfan with intermittent fludarabine provides an alternative treatment strategy that is generally well tolerated and permits an increase in total busulfan dose with encouraging efficacy. (NCI study no. NCT00448357.).

Authors
Shea, TC; Walko, C; Chung, Y; Ivanova, A; Sheets, J; Rao, K; Gabriel, D; Comeau, T; Wood, W; Coghill, J; Armistead, P; Sarantopoulos, S; Serody, J
MLA Citation
Shea, TC, Walko, C, Chung, Y, Ivanova, A, Sheets, J, Rao, K, Gabriel, D, Comeau, T, Wood, W, Coghill, J, Armistead, P, Sarantopoulos, S, and Serody, J. "Phase I/II Trial of Dose-Escalated Busulfan Delivered by Prolonged Continuous Infusion in Allogeneic Transplant Patients." Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 21.12 (December 2015): 2129-2135.
PMID
26210442
Source
epmc
Published In
Biology of Blood and Marrow Transplantation
Volume
21
Issue
12
Publish Date
2015
Start Page
2129
End Page
2135
DOI
10.1016/j.bbmt.2015.07.016

Imatinib mesylate for the treatment of steroid-refractory sclerotic-type cutaneous chronic graft-versus-host disease.

Sclerotic skin manifestations of chronic graft-versus-host disease (ScGVHD) lead to significant morbidity, including functional disability from joint range of motion (ROM) restriction. No superior second-line therapy has been established for steroid-refractory disease. Imatinib mesylate is a multikinase inhibitor of several signaling pathways implicated in skin fibrosis with in vitro antifibrotic activity. We performed an open-label pilot phase II trial of imatinib in children and adults with corticosteroid-refractory ScGVHD. Twenty patients were enrolled in a 6-month trial. Eight received a standard dose (adult, 400 mg daily; children, 260 mg/m(2) daily). Because of poor tolerability, 12 additional patients underwent a dose escalation regimen (adult, 100 mg daily initial dose up to 200 mg daily maximum; children, initial dose 65 mg/m(2) daily up to 130 mg/m(2) daily). Fourteen patients were assessable for primary response, improvement in joint ROM deficit, at 6 months. Primary outcome criteria for partial response was met in 5 of 14 (36%), stable disease in 7 of 14 (50%), and progressive disease in 2 of 14 (14%) patients. Eleven patients (79%), including 5 with partial response and 6 with stable disease, demonstrated a positive gain in ROM (range of 3% to 94% improvement in deficit). Of 13 patients with measurable changes at 6 months, the average improvement in ROM deficit was 24.2% (interquartile range, 15.5% to 30.5%; P = .011). This trial is registered at http://clinicaltrials.gov as NCT007020689.

Authors
Baird, K; Comis, LE; Joe, GO; Steinberg, SM; Hakim, FT; Rose, JJ; Mitchell, SA; Pavletic, SZ; Figg, WD; Yao, L; Flanders, KC; Takebe, N; Sarantopoulos, S; Booher, S; Cowen, EW
MLA Citation
Baird, K, Comis, LE, Joe, GO, Steinberg, SM, Hakim, FT, Rose, JJ, Mitchell, SA, Pavletic, SZ, Figg, WD, Yao, L, Flanders, KC, Takebe, N, Sarantopoulos, S, Booher, S, and Cowen, EW. "Imatinib mesylate for the treatment of steroid-refractory sclerotic-type cutaneous chronic graft-versus-host disease." Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 21.6 (June 2015): 1083-1090.
PMID
25771402
Source
epmc
Published In
Biology of Blood and Marrow Transplantation
Volume
21
Issue
6
Publish Date
2015
Start Page
1083
End Page
1090
DOI
10.1016/j.bbmt.2015.03.006

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, 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, and Blazar, BR. "Targeting Syk-activated B cells in murine and human chronic graft-versus-host disease." Blood 125.26 (June 2015): 4085-4094.
PMID
25852057
Source
epmc
Published In
Blood
Volume
125
Issue
26
Publish Date
2015
Start Page
4085
End Page
4094
DOI
10.1182/blood-2014-08-595470

Peptide/MHC Tetramer-Based Sorting of CD8+ T Cells to a Leukemia Antigen Yields Clonotypes Drawn Nonspecifically from an Underlying Restricted Repertoire

Authors
Hunsucker, SA; McGary, CS; Vincent, BG; Enyenihi, AA; Waugh, JP; McKinnon, KP; Bixby, LM; Ropp, PA; Coghill, JM; Wood, WA; Gabriel, DA; Sarantopoulos, S; Shea, TC; Serody, JS; Alatrash, G; Rodriguez-Cruz, T; Lizee, G; Buntzman, AS; Frelinger, JA; Glish, GL; Armistead, PM
MLA Citation
Hunsucker, SA, McGary, CS, Vincent, BG, Enyenihi, AA, Waugh, JP, McKinnon, KP, Bixby, LM, Ropp, PA, Coghill, JM, Wood, WA, Gabriel, DA, Sarantopoulos, S, Shea, TC, Serody, JS, Alatrash, G, Rodriguez-Cruz, T, Lizee, G, Buntzman, AS, Frelinger, JA, Glish, GL, and Armistead, PM. "Peptide/MHC Tetramer-Based Sorting of CD8+ T Cells to a Leukemia Antigen Yields Clonotypes Drawn Nonspecifically from an Underlying Restricted Repertoire." Cancer Immunology Research 3.3 (March 1, 2015): 228-235.
Source
crossref
Published In
Cancer Immunology Research
Volume
3
Issue
3
Publish Date
2015
Start Page
228
End Page
235
DOI
10.1158/2326-6066.CIR-14-0001

Aberrant B-cell homeostasis in chronic GVHD.

Recent studies have compelled further interest in the potential pathological role of B cells in chronic graft-versus-host disease (cGVHD). In patients with cGVHD, B cells are activated and primed for survival via B-cell activating factor and B-cell receptor-associated pathways. Understanding the signaling pathways that drive immune pathology in cGVHD will facilitate the development of new strategies to selectively target aberrantly activated B cells and restore normal B-cell homeostasis after allogeneic stem cell transplantation.

Authors
Sarantopoulos, S; Ritz, J
MLA Citation
Sarantopoulos, S, and Ritz, J. "Aberrant B-cell homeostasis in chronic GVHD." Blood 125.11 (March 2015): 1703-1707. (Review)
PMID
25645355
Source
epmc
Published In
Blood
Volume
125
Issue
11
Publish Date
2015
Start Page
1703
End Page
1707
DOI
10.1182/blood-2014-12-567834

Reprint of: B cells in chronic graft-versus-host disease.

Chronic graft-versus-host disease (cGVHD) continues to be a common complication of allogeneic hematopoietic stem cell transplantation. Unlike acute graft-versus-host disease, which is mediated almost entirely by donor T cells, the immune pathology of cGVHD is more complex and donor B cells have also been found to play an important role. Recent studies from several laboratories have enhanced our understanding of how donor B cells contribute to this clinical syndrome and this has led to new therapeutic opportunities. Here, Dr Sarantopoulos reviews some of the important mechanisms responsible for persistent B cell activation and loss of B cell tolerance in patients with cGVHD. Dr Blazar describes recent studies in preclinical models that have identified novel B cell-directed agents that may be effective for prevention or treatment of cGVHD. Some B cell-directed therapies have already been tested in patients with cGVHD and Dr Cutler reviews the results of these studies documenting the potential efficacy of this approach. Supported by mechanistic studies in patients and preclinical models, new B cell-directed therapies for cGVHD will now be evaluated in clinical trials.

Authors
Sarantopoulos, S; Blazar, BR; Cutler, C; Ritz, J
MLA Citation
Sarantopoulos, S, Blazar, BR, Cutler, C, and Ritz, J. "Reprint of: B cells in chronic graft-versus-host disease." Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 21.2 Suppl (February 2015): S11-S18.
PMID
25620647
Source
epmc
Published In
Biology of Blood and Marrow Transplantation
Volume
21
Issue
2 Suppl
Publish Date
2015
Start Page
S11
End Page
S18
DOI
10.1016/j.bbmt.2014.12.033

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
Fedoriw, Y, Cichon, L, Dokouhaki, P, Mathews, S, Sharf, A, and Sarantopoulos, S. "Delayed Reconstitution of Bone Marrow B Cell Precursors After Allogeneic Stem Cell Transplantation Is Associated With Chronic Graft Versus Host Disease (cGVHD)." February 2015.
Source
wos-lite
Published In
Laboratory Investigation
Volume
95
Publish Date
2015
Start Page
344A
End Page
344A

Administration of Plerixafor (a CXCR4 antagonist) Following Myeloablative Allogeneic Hematopoietic Stem Cell Transplantation Enhances Platelet Recovery in a Phase I/II Trial

Authors
Green, MMB; Horwitz, ME; Kang, Y; Chao, NJ; Long, GD; Rizzieri, D; Gasparetto, C; Sung, AD; Sarantopoulos, S; Li, Z; Corbet, K; Riggan-Stuelke, E; Sullivan, K; Wilson, B; Chhabra, S; Costa, LV; Mims, A; Stuart, R
MLA Citation
Green, MMB, Horwitz, ME, Kang, Y, Chao, NJ, Long, GD, Rizzieri, D, Gasparetto, C, Sung, AD, Sarantopoulos, S, Li, Z, Corbet, K, Riggan-Stuelke, E, Sullivan, K, Wilson, B, Chhabra, S, Costa, LV, Mims, A, and Stuart, R. "Administration of Plerixafor (a CXCR4 antagonist) Following Myeloablative Allogeneic Hematopoietic Stem Cell Transplantation Enhances Platelet Recovery in a Phase I/II Trial." February 2015.
Source
wos-lite
Published In
Biology of Blood and Marrow Transplantation
Volume
21
Issue
2
Publish Date
2015
Start Page
S31
End Page
S32

Differential Impact of Dose Escalated Busulfan on Allogeneic Transplant for High, Intermediate and Low Risk Disease

Authors
Shea, TC; Walko, CM; Chung, Y; Ivanova, A; Rao, KV; Coghill, J; Sarantopoulos, S; Wood, WA; Armistead, P; Gabriel, DA; Serody, JS
MLA Citation
Shea, TC, Walko, CM, Chung, Y, Ivanova, A, Rao, KV, Coghill, J, Sarantopoulos, S, Wood, WA, Armistead, P, Gabriel, DA, and Serody, JS. "Differential Impact of Dose Escalated Busulfan on Allogeneic Transplant for High, Intermediate and Low Risk Disease." February 2015.
Source
wos-lite
Published In
Biology of Blood and Marrow Transplantation
Volume
21
Issue
2
Publish Date
2015
Start Page
S310
End Page
S310

B cells in chronic graft-versus-host disease.

Chronic graft-versus-host disease (cGVHD) continues to be a common complication of allogeneic hematopoietic stem cell transplantation. Unlike acute graft-versus-host disease, which is mediated almost entirely by donor T cells, the immune pathology of cGVHD is more complex and donor B cells have also been found to play an important role. Recent studies from several laboratories have enhanced our understanding of how donor B cells contribute to this clinical syndrome and this has led to new therapeutic opportunities. Here, Dr Sarantopoulos reviews some of the important mechanisms responsible for persistent B cell activation and loss of B cell tolerance in patients with cGVHD. Dr Blazar describes recent studies in preclinical models that have identified novel B cell-directed agents that may be effective for prevention or treatment of cGVHD. Some B cell-directed therapies have already been tested in patients with cGVHD and Dr Cutler reviews the results of these studies documenting the potential efficacy of this approach. Supported by mechanistic studies in patients and preclinical models, new B cell-directed therapies for cGVHD will now be evaluated in clinical trials.

Authors
Sarantopoulos, S; Blazar, BR; Cutler, C; Ritz, J
MLA Citation
Sarantopoulos, S, Blazar, BR, Cutler, C, and Ritz, J. "B cells in chronic graft-versus-host disease." Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 21.1 (January 2015): 16-23. (Review)
PMID
25452031
Source
epmc
Published In
Biology of Blood and Marrow Transplantation
Volume
21
Issue
1
Publish Date
2015
Start Page
16
End Page
23
DOI
10.1016/j.bbmt.2014.10.029

Increased T follicular helper cells and germinal center B cells are required for cGVHD and bronchiolitis obliterans.

Chronic graft-versus-host disease (cGVHD) is a leading cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation. Having shown that germinal center (GC) formation and immunoglobulin deposition are required for multiorgan system cGVHD and associated bronchiolitis obliterans syndrome (BOS) in a murine model, we hypothesized that T follicular helper (Tfh) cells are necessary for cGVHD by supporting GC formation and maintenance. We show that increased frequency of Tfh cells correlated with increased GC B cells, cGVHD, and BOS. Although administering a highly depletionary anti-CD20 monoclonal antibody (mAb) to mice with established cGVHD resulted in peripheral B-cell depletion, B cells remained in the lung, and BOS was not reversed. BOS could be treated by eliminating production of interleukin-21 (IL-21) by donor T cells or IL-21 receptor (IL-21R) signaling of donor B cells. Development of BOS was dependent upon T cells expressing the chemokine receptor CXCR5 to facilitate T-cell trafficking to secondary lymphoid organ follicles. Blocking mAbs for IL-21/IL-21R, inducible T-cell costimulator (ICOS)/ICOS ligand, and CD40L/CD40 hindered GC formation and cGVHD. These data provide novel insights into cGVHD pathogenesis, indicate a role for Tfh cells in these processes, and suggest a new line of therapy using mAbs targeting Tfh cells to reverse cGVHD.

Authors
Flynn, R; Du, J; Veenstra, RG; Reichenbach, DK; Panoskaltsis-Mortari, A; Taylor, PA; Freeman, GJ; Serody, JS; Murphy, WJ; Munn, DH; Sarantopoulos, S; Luznik, L; Maillard, I; Koreth, J; Cutler, C; Soiffer, RJ; Antin, JH; Ritz, J; Dubovsky, JA; Byrd, JC; MacDonald, KP; Hill, GR; Blazar, BR
MLA Citation
Flynn, R, Du, J, Veenstra, RG, Reichenbach, DK, Panoskaltsis-Mortari, A, Taylor, PA, Freeman, GJ, Serody, JS, Murphy, WJ, Munn, DH, Sarantopoulos, S, Luznik, L, Maillard, I, Koreth, J, Cutler, C, Soiffer, RJ, Antin, JH, Ritz, J, Dubovsky, JA, Byrd, JC, MacDonald, KP, Hill, GR, and Blazar, BR. "Increased T follicular helper cells and germinal center B cells are required for cGVHD and bronchiolitis obliterans." Blood 123.25 (June 2014): 3988-3998.
PMID
24820310
Source
epmc
Published In
Blood
Volume
123
Issue
25
Publish Date
2014
Start Page
3988
End Page
3998
DOI
10.1182/blood-2014-03-562231

Post-transplantation B cell activating factor and B cell recovery before onset of chronic graft-versus-host disease.

Excessive levels of B cell activating factor (BAFF) are found in patients with active chronic graft-versus-host disease (cGVHD). In mice, BAFF has been shown to be essential for B cell recovery after myeloablation. To assess how BAFF levels relate to transplantation factors and subsequent development of cGVHD, we prospectively monitored 412 patients in the first year after allogeneic peripheral blood or bone marrow hematopoietic stem cell transplantation (HSCT) and censored data at time of cGVHD onset. In patients who did not develop cGVHD, we affirmed a temporal pattern of gradually decreasing BAFF levels as B cell numbers increase after myeloablative conditioning. In contrast, after reduced-intensity conditioning, BAFF levels remained high throughout the first post-HSCT year, suggesting that the degree of myeloablation resulted in delayed B cell recovery associated with persistence of higher BAFF levels. Given that high BAFF/B cell ratios have been associated with active cGVHD, we examined differences in early BAFF/B cell ratios and found significantly different BAFF/B cell ratios at 3 months post-HSCT only after myeloablative conditioning in patients who subsequently developed cGVHD. In addition to HSCT conditioning type, the use of sirolimus was significantly associated with higher BAFF levels after HSCT, and this also was potentially related to lower B cell numbers. Taken together, our results are important for interpreting BAFF measurements in cGVHD biomarker studies.

Authors
Jacobson, CA; Sun, L; Kim, HT; McDonough, SM; Reynolds, CG; Schowalter, M; Koreth, J; Cutler, CS; Ho, VT; Alyea, EP; Armand, P; Blazar, BR; Soiffer, RJ; Antin, JH; Ritz, J; Sarantopoulos, S
MLA Citation
Jacobson, CA, Sun, L, Kim, HT, McDonough, SM, Reynolds, CG, Schowalter, M, Koreth, J, Cutler, CS, Ho, VT, Alyea, EP, Armand, P, Blazar, BR, Soiffer, RJ, Antin, JH, Ritz, J, and Sarantopoulos, S. "Post-transplantation B cell activating factor and B cell recovery before onset of chronic graft-versus-host disease." Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 20.5 (May 2014): 668-675.
PMID
24462743
Source
epmc
Published In
Biology of Blood and Marrow Transplantation
Volume
20
Issue
5
Publish Date
2014
Start Page
668
End Page
675
DOI
10.1016/j.bbmt.2014.01.021

Increased BCR responsiveness in B cells from patients with chronic GVHD.

Although B cells have emerged as important contributors to chronic graft-versus-host-disease (cGVHD) pathogenesis, the mechanisms responsible for their sustained activation remain unknown. We previously showed that patients with cGVHD have significantly increased B cell-activating factor (BAFF) levels and that their B cells are activated and resistant to apoptosis. Exogenous BAFF confers a state of immediate responsiveness to antigen stimulation in normal murine B cells. To address this in cGVHD, we studied B-cell receptor (BCR) responsiveness in 48 patients who were >1 year out from allogeneic hematopoietic stem cell transplantation (HSCT). We found that B cells from cGVHD patients had significantly increased proliferative responses to BCR stimulation along with elevated basal levels of the proximal BCR signaling components B cell linker protein (BLNK) and Syk. After initiation of BCR signaling, cGVHD B cells exhibited increased BLNK and Syk phosphorylation compared with B cells from patients without cGVHD. Blocking Syk kinase activity prevented relative post-HSCT BCR hyper-responsiveness of cGVHD B cells. These data suggest that a lowered BCR signaling threshold in cGVHD associates with increased B-cell proliferation and activation in response to antigen. We reveal a mechanism underpinning aberrant B-cell activation in cGVHD and suggest that therapeutic inhibition of the involved kinases may benefit these patients.

Authors
Allen, JL; Tata, PV; Fore, MS; Wooten, J; Rudra, S; Deal, AM; Sharf, A; Hoffert, T; Roehrs, PA; Shea, TC; Serody, JS; Richards, KL; Jagasia, M; Lee, SJ; Rizzieri, D; Horwitz, ME; Chao, NJ; Sarantopoulos, S
MLA Citation
Allen, JL, Tata, PV, Fore, MS, Wooten, J, Rudra, S, Deal, AM, Sharf, A, Hoffert, T, Roehrs, PA, Shea, TC, Serody, JS, Richards, KL, Jagasia, M, Lee, SJ, Rizzieri, D, Horwitz, ME, Chao, NJ, and Sarantopoulos, S. "Increased BCR responsiveness in B cells from patients with chronic GVHD." Blood 123.13 (March 2014): 2108-2115.
PMID
24532806
Source
epmc
Published In
Blood
Volume
123
Issue
13
Publish Date
2014
Start Page
2108
End Page
2115
DOI
10.1182/blood-2013-10-533562

BAFF-ling autoantibodies.

There is emerging evidence that autoantibodies directed against cytokines modulate the severity of autoimmune disease. Identification of cytokine-targeted autoantibodies in patients can be informative for diagnosis and predicting clinical outcome. In this issue of the JCI, Price and colleagues used a multiplex protein microarray to identify autoantibodies in serum from SLE patients. They found autoantibodies directed against the B cell-activating factor (BAFF) were associated with greater disease severity. This study highlights the contribution of cytokine-directed autoantibodies in disease and describes a valuable tool for identifying autoantibodies against serum antigens.

Authors
Sarantopoulos, S; Su, MA
MLA Citation
Sarantopoulos, S, and Su, MA. "BAFF-ling autoantibodies." J Clin Invest 123.12 (December 2013): 5006-5008.
PMID
24270413
Source
pubmed
Published In
Journal of Clinical Investigation
Volume
123
Issue
12
Publish Date
2013
Start Page
5006
End Page
5008
DOI
10.1172/JCI73166

Rituximab prophylaxis prevents corticosteroid-requiring chronic GVHD after allogeneic peripheral blood stem cell transplantation: results of a phase 2 trial.

B cells are implicated in the pathophysiology of chronic graft-vs-host disease (GVHD), and phase 2 trials suggest that B cell depletion can treat established chronic GVHD. We hypothesized that posttransplantation B cell depletion could prevent the occurrence of chronic GVHD. We performed a 65-patient phase 2 trial of rituximab (375 mg/m(2) IV), administered at 3, 6, 9, and 12 months after transplantation. Rituximab administration was safe without severe infusional adverse events. The cumulative incidences of chronic GVHD and systemic corticosteroid-requiring chronic GVHD at 2 years from transplantation were 48% and 31%, respectively, both lower than the corresponding rates in a concurrent control cohort (60%, P = .1, and 48.5%, P = .015). There was no difference in relapse incidence, but treatment-related mortality at 4 years from transplantation was significantly lower in treated subjects when compared with controls (5% vs 19%, P = .02), and overall survival was superior at 4 years (71% vs 56%, P = .05). At 2 years from transplantation, the B-cell activating factor/B-cell ratio was significantly higher in subjects who developed chronic GVHD in comparison with those without chronic GVHD (P = .039). Rituximab can prevent systemic corticosteroid-requiring chronic GVHD after peripheral blood stem cell transplantation and should be tested in a prospective randomized trial.

Authors
Cutler, C; Kim, HT; Bindra, B; Sarantopoulos, S; Ho, VT; Chen, Y-B; Rosenblatt, J; McDonough, S; Watanaboonyongcharoen, P; Armand, P; Koreth, J; Glotzbecker, B; Alyea, E; Blazar, BR; Soiffer, RJ; Ritz, J; Antin, JH
MLA Citation
Cutler, C, Kim, HT, Bindra, B, Sarantopoulos, S, Ho, VT, Chen, Y-B, Rosenblatt, J, McDonough, S, Watanaboonyongcharoen, P, Armand, P, Koreth, J, Glotzbecker, B, Alyea, E, Blazar, BR, Soiffer, RJ, Ritz, J, and Antin, JH. "Rituximab prophylaxis prevents corticosteroid-requiring chronic GVHD after allogeneic peripheral blood stem cell transplantation: results of a phase 2 trial." Blood 122.8 (August 2013): 1510-1517.
PMID
23861248
Source
epmc
Published In
Blood
Volume
122
Issue
8
Publish Date
2013
Start Page
1510
End Page
1517
DOI
10.1182/blood-2013-04-495895

Effectiveness of etoposide chemomobilization in lymphoma patients undergoing auto-SCT.

The effectiveness of stem cell mobilization with G-CSF in lymphoma patients is suboptimal. We reviewed our institutional experience using chemomobilization with etoposide (VP-16; 375 mg/m(2) on days +1 and +2) and G-CSF (5 μg/kg twice daily from day +3 through the final day of collection) in 159 patients with lymphoma. This approach resulted in successful mobilization (>2 × 10(6) CD34+ cells collected) in 94% of patients (83% within 4 apheresis sessions). Fifty-seven percent of patients yielded at least 5 × 10(6) cells in 2 days and were defined as good mobilizers. The regimen was safe with a low rate of rehospitalization. Average costs were $14 923 for good mobilizers and $27 044 for poor mobilizers (P<0.05). Using our data, we performed a 'break-even' analysis that demonstrated that adding two doses of Plerixafor to predicted poor mobilizers at the time of first CD34+ cell count would achieve cost neutrality if the frequency of good mobilizers were to increase by 21%, while the frequency of good mobilizers would need to increase by 25% if three doses of Plerixafor were used. We conclude that chemomobilization with etoposide and G-CSF in patients with lymphoma is effective, with future opportunities for cost-neutral improvement using novel agents.

Authors
Wood, WA; Whitley, J; Goyal, R; Brown, PM; Sharf, A; Irons, R; Rao, KV; Essenmacher, A; Serody, JS; Coghill, JM; Armistead, PM; Sarantopoulos, S; Gabriel, DA; Shea, TC
MLA Citation
Wood, WA, Whitley, J, Goyal, R, Brown, PM, Sharf, A, Irons, R, Rao, KV, Essenmacher, A, Serody, JS, Coghill, JM, Armistead, PM, Sarantopoulos, S, Gabriel, DA, and Shea, TC. "Effectiveness of etoposide chemomobilization in lymphoma patients undergoing auto-SCT." Bone marrow transplantation 48.6 (June 2013): 771-776.
PMID
23165501
Source
epmc
Published In
Bone Marrow Transplantation
Volume
48
Issue
6
Publish Date
2013
Start Page
771
End Page
776
DOI
10.1038/bmt.2012.216

Increased BLNK and Syk in B Cells From Chronic Graft-Versus-Host Disease Patients: Identification of Novel Therapeutic Targets

Authors
Allen, JL; Fedoriw, G; Wooten, J; Fore, M; Roehrs, PA; Armistead, P; Coghill, J; Shea, TC; Richards, K; Lee, SJ; Rowe, K; Rizzieri, D; Chao, NJ; Serody, JS; Sarantopoulos, S
MLA Citation
Allen, JL, Fedoriw, G, Wooten, J, Fore, M, Roehrs, PA, Armistead, P, Coghill, J, Shea, TC, Richards, K, Lee, SJ, Rowe, K, Rizzieri, D, Chao, NJ, Serody, JS, and Sarantopoulos, S. "Increased BLNK and Syk in B Cells From Chronic Graft-Versus-Host Disease Patients: Identification of Novel Therapeutic Targets." February 2013.
Source
wos-lite
Published In
Biology of Blood and Marrow Transplantation
Volume
19
Issue
2
Publish Date
2013
Start Page
S136
End Page
S137

Feasibility and Prognostic Value of VO2(peak) in Patients Undergoing Hematopoietic Cell Transplantation (HCT)

Authors
Wood, WA; Deal, AM; Battaglini, CL; Reeve, BB; Abernethy, AP; Kim, YH; Whitley, JS; Shatten, C; Irons, RN; Essenmacher, AN; Wehner, K; Pinto, A; Coghill, J; Armistead, PM; Sarantopoulos, S; Gabriel, DA; Serody, JS; Shea, TC
MLA Citation
Wood, WA, Deal, AM, Battaglini, CL, Reeve, BB, Abernethy, AP, Kim, YH, Whitley, JS, Shatten, C, Irons, RN, Essenmacher, AN, Wehner, K, Pinto, A, Coghill, J, Armistead, PM, Sarantopoulos, S, Gabriel, DA, Serody, JS, and Shea, TC. "Feasibility and Prognostic Value of VO2(peak) in Patients Undergoing Hematopoietic Cell Transplantation (HCT)." November 16, 2012.
Source
wos-lite
Published In
Blood
Volume
120
Issue
21
Publish Date
2012

Feasibility of Daily and Weekly Symptom and Health-Related Quality of Life (HRQOL) Surveillance in Patients Receiving Hematopoietic Cell Transplantation (HCT)

Authors
Wood, WA; Deal, AM; Reeve, BB; Abernethy, AP; Battaglini, CL; Kim, YH; Whitley, JS; Shatten, C; Irons, RN; Essenmacher, AN; Wehner, K; Pinto, A; Coghill, J; Armistead, PM; Sarantopoulos, S; Gabriel, DA; Serody, JS; Shea, TC
MLA Citation
Wood, WA, Deal, AM, Reeve, BB, Abernethy, AP, Battaglini, CL, Kim, YH, Whitley, JS, Shatten, C, Irons, RN, Essenmacher, AN, Wehner, K, Pinto, A, Coghill, J, Armistead, PM, Sarantopoulos, S, Gabriel, DA, Serody, JS, and Shea, TC. "Feasibility of Daily and Weekly Symptom and Health-Related Quality of Life (HRQOL) Surveillance in Patients Receiving Hematopoietic Cell Transplantation (HCT)." November 16, 2012.
Source
wos-lite
Published In
Blood
Volume
120
Issue
21
Publish Date
2012

B cells from patients with chronic GVHD are activated and primed for survival via BAFF-mediated pathways.

Recent data reveal an important role for B cells in the pathogenesis of chronic GVHD (cGVHD). Patients with cGVHD have delayed B-cell reconstitution and elevated BAFF to B-cell ratios compared to patients without cGVHD. The mechanisms promoting and sustaining B-cell activation in this disease, however, remain unknown. As BAFF increases murine B-cell metabolism and survival and maintains autoreactive B-cell clones, we performed ex vivo analyses of peripheral B cells from 51 patients who either had or did not have active cGVHD and were greater than 1 year from the time of allogeneic hematopoietic stem cell transplantation. We found that B cells from patients with active cGVHD were in a heightened metabolic state and were resistant to apoptosis. Exogenous BAFF treatment amplified cell size and survival in B cells from these patients. We found significantly increased signaling through ERK and AKT that associated with decreased levels of proapoptotic Bim, suggesting a mechanistic link between elevated BAFF levels and aberrant B-cell survival. Thus, we identify a role for BAFF in the pathogenesis of cGVHD and define B-cell activation and survival pathways suitable for novel therapeutic development in cGVHD.

Authors
Allen, JL; Fore, MS; Wooten, J; Roehrs, PA; Bhuiya, NS; Hoffert, T; Sharf, A; Deal, AM; Armistead, P; Coghill, J; Gabriel, DA; Irons, R; Essenmacher, A; Shea, TC; Richards, K; Cutler, C; Ritz, J; Serody, J; Baldwin, AS; Sarantopoulos, S
MLA Citation
Allen, JL, Fore, MS, Wooten, J, Roehrs, PA, Bhuiya, NS, Hoffert, T, Sharf, A, Deal, AM, Armistead, P, Coghill, J, Gabriel, DA, Irons, R, Essenmacher, A, Shea, TC, Richards, K, Cutler, C, Ritz, J, Serody, J, Baldwin, AS, and Sarantopoulos, S. "B cells from patients with chronic GVHD are activated and primed for survival via BAFF-mediated pathways." Blood 120.12 (September 2012): 2529-2536.
PMID
22896003
Source
epmc
Published In
Blood
Volume
120
Issue
12
Publish Date
2012
Start Page
2529
End Page
2536
DOI
10.1182/blood-2012-06-438911

Further examination of BAFF SNPs in cGVHD.

Authors
Fore, M; Jagasia, M; Sarantopoulos, S; Richards, KL
MLA Citation
Fore, M, Jagasia, M, Sarantopoulos, S, and Richards, KL. "Further examination of BAFF SNPs in cGVHD." Blood 120.3 (July 2012): 700-701.
PMID
22822003
Source
epmc
Published In
Blood
Volume
120
Issue
3
Publish Date
2012
Start Page
700
End Page
701
DOI
10.1182/blood-2012-05-428409

Bone marrow B cell precursor number after allogeneic stem cell transplantation and GVHD development.

Patients without chronic graft-versus-host disease (cGVHD) have robust B cell reconstitution and are able to maintain B cell homeostasis after allogeneic hematopoietic stem cell transplantation (HSCT). To determine whether B lymphopoiesis differs before cGVHD develops, we examined bone marrow (BM) biopsies for terminal deoxynucleotidyl transferase (TdT) and PAX5 immunostaining early post-HSCT at day 30 when all patients have been shown to have high B cell activating factor (BAFF) levels. We found significantly greater numbers of BM B cell precursors in patients who did not develop cGVHD compared with those who developed cGVHD (median = 44 vs 2 cells/high powered field [hpf]; respectively; P < .001). Importantly, a significant increase in precursor B cells was maintained when patients receiving high-dose steroid therapy were excluded (median = 49 vs 20 cells/hpf; P = .017). Thus, we demonstrate the association of BM B cell production capacity in human GVHD development. Increased BM precursor B cell number may serve to predict good clinical outcome after HSCT.

Authors
Fedoriw, Y; Samulski, TD; Deal, AM; Dunphy, CH; Sharf, A; Shea, TC; Serody, JS; Sarantopoulos, S
MLA Citation
Fedoriw, Y, Samulski, TD, Deal, AM, Dunphy, CH, Sharf, A, Shea, TC, Serody, JS, and Sarantopoulos, S. "Bone marrow B cell precursor number after allogeneic stem cell transplantation and GVHD development." Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 18.6 (June 2012): 968-973.
PMID
22446015
Source
epmc
Published In
Biology of Blood and Marrow Transplantation
Volume
18
Issue
6
Publish Date
2012
Start Page
968
End Page
973
DOI
10.1016/j.bbmt.2012.03.005

Clinical applications for biomarkers of acute and chronic graft-versus-host disease.

Acute and chronic graft-versus-host disease (aGVHD, cGVHD) are serious complications of allogeneic hematopoietic cell transplantation. The complex pathophysiology of these disease processes is associated with immune system activation, the release of cytokines and chemokines, and alterations in cell populations. The blood levels of specific protein and cellular levels in patients with GVHD have correlated with the development, diagnosis, and prognosis of GVHD. Here, we review the most promising biomarkers for aGVHD and cGVHD with clinical relevance. The utility of GVHD biomarkers in clinical care of allogeneic hematopoietic cell transplantation recipients needs to be proven through clinical trials, and potential approaches to trial design are discussed.

Authors
Levine, JE; Paczesny, S; Sarantopoulos, S
MLA Citation
Levine, JE, Paczesny, S, and Sarantopoulos, S. "Clinical applications for biomarkers of acute and chronic graft-versus-host disease." Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 18.1 Suppl (January 2012): S116-S124. (Review)
PMID
22226094
Source
epmc
Published In
Biology of Blood and Marrow Transplantation
Volume
18
Issue
1 Suppl
Publish Date
2012
Start Page
S116
End Page
S124
DOI
10.1016/j.bbmt.2011.10.019

Combined CD4 T-cell and antibody response to human minor histocompatibility antigen DBY after allogeneic stem-cell transplantation.

Antibody responses to HY antigens in male recipients are frequent after transplantation of stem cells from female donors (Miklos et al., Blood 2005; 105: 2973; Miklos et al., Blood 2004; 103: 353). However, evidence that this B-cell immunity is accompanied by T-cell responses to the cognate antigens is scarce. Here, we examined T- and B-cell responses to DBY antigen in a male patient who received hematopoietic stem cells from a human leukocyte antigen-identical female sibling.We used 93 overlapping peptides representing the entire DBY protein to detect and characterize T-cell and antibody responses to DBY by enzyme-linked immunosorbent spot (ELISPOT) and enzyme-linked immunosorbent assay.High frequency CD4+ T cells specific for a unique DBY peptide were detected in the patient blood. We isolated the corresponding T-cell clone and characterized the recognized epitope as an 18-mer peptide restricted by human leukocyte antigen-DRB1*0101. Upon stimulation, this clone produced cytokines with no evidence of Th1 or Th2 polarization. Remarkably, this clone also recognized the DBX homologue peptide and responded to female donor dendritic cells stimulated with poly I/C or lipopolysaccharide, indicating that the peptide was endogenously processed in these cells. High titer DBY-specific antibodies were also found in the patient serum which, in contrast to the T-cell response, did not cross-react with DBX.We show here the development of a coordinated B and T-cell response to DBY in a recipient of sex mismatched allogeneic hematopoietic stem-cell transplantation. Our findings support a role for CD4+ T cells in the development of humoral immunity to minor histocompatibility antigens.

Authors
Porcheray, F; Miklos, DB; Floyd, BH; Sarantopoulos, S; Bellucci, R; Soiffer, RJ; Antin, JH; Alyea, EP; Ritz, J; Zorn, E
MLA Citation
Porcheray, F, Miklos, DB, Floyd, BH, Sarantopoulos, S, Bellucci, R, Soiffer, RJ, Antin, JH, Alyea, EP, Ritz, J, and Zorn, E. "Combined CD4 T-cell and antibody response to human minor histocompatibility antigen DBY after allogeneic stem-cell transplantation." Transplantation 92.3 (August 2011): 359-365.
PMID
21709606
Source
epmc
Published In
Transplantation
Volume
92
Issue
3
Publish Date
2011
Start Page
359
End Page
365
DOI
10.1097/tp.0b013e3182244cc3

Effector CD4+ T cells, the cytokines they generate, and GVHD: something old and something new.

GVHD is a syndrome that results from minor and major histocompatibility complex incompatibilities between the donor and recipient. More than 50 years after its initial description, the pathophysiology of GVHD remains poorly understood. Nonetheless, donor T cells have been shown to be critical to the pathophysiology of acute and chronic GVHD, yet precisely how they function remains unclear. The effector mechanisms by which donor T cells mediate tissue inflammation is even less well understood. Identification of several new lineages of CD4(+) T cells made in the past decade and their roles in the pathophysiology of T cell-mediated diseases has shed new light on these effector mechanisms. In this review, we summarize the recent descriptions of these T-cell lineages and the current data supporting their role in acute and to a lesser extent chronic GVHD. Investigations into the activity of these new T-cell lineages may provide more rationale approaches to the treatment or prevention of GVHD.

Authors
Coghill, JM; Sarantopoulos, S; Moran, TP; Murphy, WJ; Blazar, BR; Serody, JS
MLA Citation
Coghill, JM, Sarantopoulos, S, Moran, TP, Murphy, WJ, Blazar, BR, and Serody, JS. "Effector CD4+ T cells, the cytokines they generate, and GVHD: something old and something new." Blood 117.12 (March 2011): 3268-3276. (Review)
PMID
21245483
Source
epmc
Published In
Blood
Volume
117
Issue
12
Publish Date
2011
Start Page
3268
End Page
3276
DOI
10.1182/blood-2010-12-290403

Recovery of B-cell homeostasis after rituximab in chronic graft-versus-host disease.

Investigation of the effects of rituximab (anti-CD20) on B-cell-activating factor of the tumor necrosis factor family (BAFF) and B cells would better define the significance of B-cell homeostasis in chronic graft-versus-host disease (cGVHD) pathophysiology. We studied 20 cGVHD patients at a median of 25 months after rituximab treatment when most patients had recovered total B-cell numbers. A total of 55% of patients had stable/improved cGVHD, and total B-cell numbers in these patients were significantly higher compared with rituximab-unresponsive patients. Although total B-cell number did not differ significantly between cGVHD groups before rituximab, there was a proportional increase in B-cell precursors in patients who later had stable/improved cGVHD. After rituximab, BAFF levels increased in all patients. Coincident with B-cell recovery in the stable/improved group, BAFF/B-cell ratios and CD27(+) B-cell frequencies decreased significantly. The peripheral B-cell pool in stable/improved cGVHD patients was largely composed of naive IgD(+) B cells. By contrast, rituximab-unresponsive cGVHD patients had persistent elevation of BAFF and a predominance of circulating B cells possessing an activated BAFF-R(Lo)CD20(Lo) cell surface phenotype. Thus, naive B-cell reconstitution and decreased BAFF/B-cell ratios were associated with clinical response after rituximab in cGVHD. Our findings begin to delineate B-cell homeostatic mechanisms important for human immune tolerance.

Authors
Sarantopoulos, S; Stevenson, KE; Kim, HT; Washel, WS; Bhuiya, NS; Cutler, CS; Alyea, EP; Ho, VT; Soiffer, RJ; Antin, JH; Ritz, J
MLA Citation
Sarantopoulos, S, Stevenson, KE, Kim, HT, Washel, WS, Bhuiya, NS, Cutler, CS, Alyea, EP, Ho, VT, Soiffer, RJ, Antin, JH, and Ritz, J. "Recovery of B-cell homeostasis after rituximab in chronic graft-versus-host disease." Blood 117.7 (February 2011): 2275-2283.
PMID
21097674
Source
epmc
Published In
Blood
Volume
117
Issue
7
Publish Date
2011
Start Page
2275
End Page
2283
DOI
10.1182/blood-2010-10-307819

Common minor histocompatibility antigen discovery based upon patient clinical outcomes and genomic data.

Minor histocompatibility antigens (mHA) mediate much of the graft vs. leukemia (GvL) effect and graft vs. host disease (GvHD) in patients who undergo allogeneic stem cell transplantation (SCT). Therapeutic decision making and treatments based upon mHAs will require the evaluation of multiple candidate mHAs and the selection of those with the potential to have the greatest impact on clinical outcomes. We hypothesized that common, immunodominant mHAs, which are presented by HLA-A, B, and C molecules, can mediate clinically significant GvL and/or GvHD, and that these mHAs can be identified through association of genomic data with clinical outcomes.Because most mHAs result from donor/recipient cSNP disparities, we genotyped 57 myeloid leukemia patients and their donors at 13,917 cSNPs. We correlated the frequency of genetically predicted mHA disparities with clinical evidence of an immune response and then computationally screened all peptides mapping to the highly associated cSNPs for their ability to bind to HLA molecules. As proof-of-concept, we analyzed one predicted antigen, T4A, whose mHA mismatch trended towards improved overall and disease free survival in our cohort. T4A mHA mismatches occurred at the maximum theoretical frequency for any given SCT. T4A-specific CD8+ T lymphocytes (CTLs) were detected in 3 of 4 evaluable post-transplant patients predicted to have a T4A mismatch.Our method is the first to combine clinical outcomes data with genomics and bioinformatics methods to predict and confirm a mHA. Refinement of this method should enable the discovery of clinically relevant mHAs in the majority of transplant patients and possibly lead to novel immunotherapeutics.

Authors
Armistead, PM; Liang, S; Li, H; Lu, S; Van Bergen, CAM; Alatrash, G; St John, L; Hunsucker, SA; Sarantopoulos, S; Falkenburg, JHF; Molldrem, JJ
MLA Citation
Armistead, PM, Liang, S, Li, H, Lu, S, Van Bergen, CAM, Alatrash, G, St John, L, Hunsucker, SA, Sarantopoulos, S, Falkenburg, JHF, and Molldrem, JJ. "Common minor histocompatibility antigen discovery based upon patient clinical outcomes and genomic data." PloS one 6.8 (January 2011): e23217-.
PMID
21858034
Source
epmc
Published In
PloS one
Volume
6
Issue
8
Publish Date
2011
Start Page
e23217
DOI
10.1371/journal.pone.0023217

Diverse patterns of T-cell response against multiple newly identified human Y chromosome-encoded minor histocompatibility epitopes.

Donor T cells respond to minor histocompatibility antigens (mHA), resulting in both graft-versus-host disease and graft versus leukemia after allogeneic hematopoietic stem cell transplantation. Because relatively few mHAs are known, we developed a new approach to predict and subsequently validate candidate mHA.We developed an algorithm based on genetic disparities between Y chromosome-encoded and X chromosome-encoded proteins and known requirements for binding to HLA class I molecules to predict Y chromosome-derived, HLA A*0201-restricted peptides (HY) and ranked peptides based on potential immunogenicity. We evaluated T-cell responses to 41 candidate peptides in 28 male recipients with female donors (FM), 22 male recipients with male donors (MM), and 26 normal individuals. All patients and donors were HLA A*0201 positive.Thirteen peptides derived from five proteins elicited significantly greater T-cell responses in FM patients compared with MM patients and in normal females compared with normal males. Six peptides were more immunogenic than the only previously known HLA A*0201-restricted Y-encoded mHA. Twenty-seven of 28 FM patients responded to at least one HY peptide, but despite a common Y chromosome mismatch and expression of HLA A*0201, each patient responded to a unique set of peptides.Novel HLA A*0201-restricted HY epitopes can be predicted and validated in patients after allogeneic hematopoietic stem cell transplantation. Highly diverse patterns of T-cell response against these epitopes have been identified. Prospective monitoring of responses to large panels of immunogenic peptides can facilitate the identification of clinically relevant targets of graft-versus-host disease and graft versus leukemia.

Authors
Ofran, Y; Kim, HT; Brusic, V; Blake, L; Mandrell, M; Wu, CJ; Sarantopoulos, S; Bellucci, R; Keskin, DB; Soiffer, RJ; Antin, JH; Ritz, J
MLA Citation
Ofran, Y, Kim, HT, Brusic, V, Blake, L, Mandrell, M, Wu, CJ, Sarantopoulos, S, Bellucci, R, Keskin, DB, Soiffer, RJ, Antin, JH, and Ritz, J. "Diverse patterns of T-cell response against multiple newly identified human Y chromosome-encoded minor histocompatibility epitopes." Clinical cancer research : an official journal of the American Association for Cancer Research 16.5 (March 2010): 1642-1651.
PMID
20160060
Source
epmc
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
16
Issue
5
Publish Date
2010
Start Page
1642
End Page
1651
DOI
10.1158/1078-0432.ccr-09-2701

Biologic activity of irradiated, autologous, GM-CSF-secreting leukemia cell vaccines early after allogeneic stem cell transplantation.

Through an immune-mediated graft-versus-leukemia effect, allogeneic hematopoietic stem cell transplantation (HSCT) affords durable clinical benefits for many patients with hematologic malignancies. Nonetheless, subjects with high-risk acute myeloid leukemia or advanced myelodysplasia often relapse, underscoring the need to intensify tumor immunity within this cohort. In preclinical models, allogeneic HSCT followed by vaccination with irradiated tumor cells engineered to secrete GM-CSF generates a potent antitumor effect without exacerbating the toxicities of graft-versus-host disease (GVHD). To test whether this strategy might be similarly active in humans, we conducted a Phase I clinical trial in which high-risk acute myeloid leukemia or myelodysplasia patients were immunized with irradiated, autologous, GM-CSF-secreting tumor cells early after allogeneic, nonmyeloablative HSCT. Despite the administration of a calcineurin inhibitor as prophylaxis against GVHD, vaccination elicited local and systemic reactions that were qualitatively similar to those previously observed in nontransplanted, immunized solid-tumor patients. While the frequencies of acute and chronic GVHD were not increased, 9 of 10 subjects who completed vaccination achieved durable complete remissions, with a median follow-up of 26 months (range 12-43 months). Six long-term responders showed marked decreases in the levels of soluble NKG2D ligands, and 3 demonstrated normalization of cytotoxic lymphocyte NKG2D expression as a function of treatment. Together, these results establish the safety and immunogenicity of irradiated, autologous, GM-CSF-secreting leukemia cell vaccines early after allogeneic HSCT, and raise the possibility that this combinatorial immunotherapy might potentiate graft-versus-leukemia in patients.

Authors
Ho, VT; Vanneman, M; Kim, H; Sasada, T; Kang, YJ; Pasek, M; Cutler, C; Koreth, J; Alyea, E; Sarantopoulos, S; Antin, JH; Ritz, J; Canning, C; Kutok, J; Mihm, MC; Dranoff, G; Soiffer, R
MLA Citation
Ho, VT, Vanneman, M, Kim, H, Sasada, T, Kang, YJ, Pasek, M, Cutler, C, Koreth, J, Alyea, E, Sarantopoulos, S, Antin, JH, Ritz, J, Canning, C, Kutok, J, Mihm, MC, Dranoff, G, and Soiffer, R. "Biologic activity of irradiated, autologous, GM-CSF-secreting leukemia cell vaccines early after allogeneic stem cell transplantation." Proceedings of the National Academy of Sciences of the United States of America 106.37 (September 2009): 15825-15830.
PMID
19717467
Source
epmc
Published In
Proceedings of the National Academy of Sciences of USA
Volume
106
Issue
37
Publish Date
2009
Start Page
15825
End Page
15830
DOI
10.1073/pnas.0908358106

Altered B-cell homeostasis and excess BAFF in human chronic graft-versus-host disease.

Chronic graft-versus-host disease (cGVHD) causes significant morbidity and mortality in patients otherwise cured of malignancy after hematopoietic stem cell transplantation (HSCT). The presence of alloantibodies and high plasma B cell-activating factor (BAFF) levels in patients with cGVHD suggest that B cells play a role in disease pathogenesis. We performed detailed phenotypic and functional analyses of peripheral B cells in 82 patients after HSCT. Patients with cGVHD had significantly higher BAFF/B-cell ratios compared with patients without cGVHD or healthy donors. In cGVHD, increasing BAFF concentrations correlated with increased numbers of circulating pre-germinal center (GC) B cells and post-GC "plasmablast-like" cells, suggesting in vivo BAFF dependence of these 2 CD27(+) B-cell subsets. Circulating CD27(+) B cells in cGVHD comprised in vivo activated B cells capable of IgG production without requiring additional antigen stimulation. Serial studies revealed that patients who subsequently developed cGVHD had delayed reconstitution of naive B cells despite persistent BAFF elevation as well as proportional increase in CD27(+) B cells in the first year after HSCT. These studies delineate specific abnormalities of B-cell homeostasis in patients with cGVHD and suggest that BAFF targeting agents may be useful in this disease.

Authors
Sarantopoulos, S; Stevenson, KE; Kim, HT; Cutler, CS; Bhuiya, NS; Schowalter, M; Ho, VT; Alyea, EP; Koreth, J; Blazar, BR; Soiffer, RJ; Antin, JH; Ritz, J
MLA Citation
Sarantopoulos, S, Stevenson, KE, Kim, HT, Cutler, CS, Bhuiya, NS, Schowalter, M, Ho, VT, Alyea, EP, Koreth, J, Blazar, BR, Soiffer, RJ, Antin, JH, and Ritz, J. "Altered B-cell homeostasis and excess BAFF in human chronic graft-versus-host disease." Blood 113.16 (April 2009): 3865-3874.
PMID
19168788
Source
epmc
Published In
Blood
Volume
113
Issue
16
Publish Date
2009
Start Page
3865
End Page
3874
DOI
10.1182/blood-2008-09-177840

Concerted potent humoral immune responses to autoantigens are associated with tumor destruction and favorable clinical outcomes without autoimmunity.

The therapeutic importance of immune responses against single versus multiple antigens is poorly understood. There also remains insufficient understanding whether responses to one subset of antigens are more significant than another. Autoantibodies are frequent in cancer patients. They can pose no biological significance or lead to debilitating paraneoplastic syndromes. Autoreactivity has been associated with clinical benefits, but the magnitude necessary for meaningful results is unknown. Autologous tumor cells engineered to secrete granulocyte macrophage colony-stimulating factor generate immune infiltrates in preexisting metastases with associated tumor destruction. We sought to identify targets of responses from this vaccination strategy.Postvaccination sera used in screening a cDNA expression library prepared from a densely infiltrated metastasis of a long-term surviving melanoma patient identified several autoantigens. Additional autoantigens were identified through similar screenings in non-small cell lung cancer and murine models, and proteins implicated in cancer propagation. ELISAs for several targets were established using recombinant proteins, whereas others were evaluated by petit serologies.Eleven gene products were identified through serologic screening from two patients showing highly favorable clinical outcomes. A subset of antigens revealed significant changes in antibody titers compared with weak responses to other proteins. Time course analyses showed coordinated enhanced titers against several targets as a function of vaccination in responding patients.This study shows the range of biologically significant antigens resulting from a whole-cell vaccine. Targets include autoantigens that are components of cell cycle regulation. Potent antibody responses against multiple autoantigens are associated with effective tumor destruction without clinical autoimmunity.

Authors
Sittler, T; Zhou, J; Park, J; Yuen, NK; Sarantopoulos, S; Mollick, J; Salgia, R; Giobbie-Hurder, A; Dranoff, G; Hodi, FS
MLA Citation
Sittler, T, Zhou, J, Park, J, Yuen, NK, Sarantopoulos, S, Mollick, J, Salgia, R, Giobbie-Hurder, A, Dranoff, G, and Hodi, FS. "Concerted potent humoral immune responses to autoantigens are associated with tumor destruction and favorable clinical outcomes without autoimmunity." Clinical cancer research : an official journal of the American Association for Cancer Research 14.12 (June 2008): 3896-3905.
PMID
18559611
Source
epmc
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
14
Issue
12
Publish Date
2008
Start Page
3896
End Page
3905
DOI
10.1158/1078-0432.ccr-07-4782

High levels of B-cell activating factor in patients with active chronic graft-versus-host disease.

Recent studies suggest that donor B cells as well as T cells contribute to immune pathology in patients with chronic graft-versus-host disease (GVHD). B-cell activating factor (BAFF) promotes survival and differentiation of activated B cells. Thus, we tested whether BAFF correlated with chronic GVHD disease activity and time of onset after allogeneic hematopoietic stem cell transplantation (HSCT).Patients who had undergone allogeneic HSCT between 1994 and 2005 for hematologic malignancies were studied. ELISA was used to measure plasma BAFF levels and flow cytometry was used to assess BAFF receptor expression on B cells in patients with or without chronic GVHD.In 104 patients, BAFF levels were significantly higher in patients with active chronic GVHD compared with those without disease (P = 0.02 and 0.0004, respectively). Treatment with high-dose prednisone (>or=30 mg/d) was associated with reduced BAFF levels in patients with active chronic GVHD (P = 0.0005). Serial studies in 24 patients showed that BAFF levels were high in the first 3 months after HSCT but subsequently decreased in 13 patients who never developed chronic GVHD. In contrast, BAFF levels remained elevated in 11 patients who developed chronic GVHD. Six-month BAFF levels >or=10 ng/mL were strongly associated with subsequent development of chronic GVHD (P < 0.0001). Following transplant, plasma BAFF levels correlated inversely with BAFF receptor expression on B cells (P = 0.01), suggesting that soluble BAFF affected B cells through this receptor.These results suggest that elevated BAFF levels contribute to B-cell activation in patients with active chronic GVHD.

Authors
Sarantopoulos, S; Stevenson, KE; Kim, HT; Bhuiya, NS; Cutler, CS; Soiffer, RJ; Antin, JH; Ritz, J
MLA Citation
Sarantopoulos, S, Stevenson, KE, Kim, HT, Bhuiya, NS, Cutler, CS, Soiffer, RJ, Antin, JH, and Ritz, J. "High levels of B-cell activating factor in patients with active chronic graft-versus-host disease." Clinical cancer research : an official journal of the American Association for Cancer Research 13.20 (October 2007): 6107-6114.
PMID
17947475
Source
epmc
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
13
Issue
20
Publish Date
2007
Start Page
6107
End Page
6114
DOI
10.1158/1078-0432.ccr-07-1290

Qa-1 restriction of CD8+ suppressor T cells.

There is increasing evidence that the immune response can be inhibited by several T cell subsets, including NK T cells, CD25+CD4+ T cells, and a subpopulation of CD8+ T cells. Animal model studies of multiple sclerosis have suggested an important role for suppressor CD8+ T cells in protection against disease recurrence and exacerbation. The molecular lynchpin of CD8+ suppressive activity is the murine MHC molecule Qa-1, termed HLA-E in humans. Here we summarize findings from work on Qa-1 that have begun to delineate suppressor CD8+ T cells and their mechanisms of action in the context of self tolerance and autoimmune disease.

Authors
Sarantopoulos, S; Lu, L; Cantor, H
MLA Citation
Sarantopoulos, S, Lu, L, and Cantor, H. "Qa-1 restriction of CD8+ suppressor T cells." The Journal of clinical investigation 114.9 (November 2004): 1218-1221. (Review)
PMID
15520850
Source
epmc
Published In
Journal of Clinical Investigation
Volume
114
Issue
9
Publish Date
2004
Start Page
1218
End Page
1221
DOI
10.1172/jci23152

Fatal hepatic necrosis following imatinib mesylate therapy.

Authors
Lin, NU; Sarantopoulos, S; Stone, JR; Galinsky, I; Stone, RM; Deangelo, DJ; Soiffer, RJ
MLA Citation
Lin, NU, Sarantopoulos, S, Stone, JR, Galinsky, I, Stone, RM, Deangelo, DJ, and Soiffer, RJ. "Fatal hepatic necrosis following imatinib mesylate therapy." Blood 102.9 (November 2003): 3455-3456.
PMID
14568907
Source
epmc
Published In
Blood
Volume
102
Issue
9
Publish Date
2003
Start Page
3455
End Page
3456
DOI
10.1182/blood-2003-07-2323

Construction of polyclonal antibody libraries using phage display.

Authors
Sharon, J; Sompuram, SR; Yang, C-Y; Williams, BR; Sarantopoulos, S
MLA Citation
Sharon, J, Sompuram, SR, Yang, C-Y, Williams, BR, and Sarantopoulos, S. "Construction of polyclonal antibody libraries using phage display." Methods in molecular biology (Clifton, N.J.) 178 (January 2002): 101-112.
PMID
11968479
Source
epmc
Published In
Methods in molecular biology (Clifton, N.J.)
Volume
178
Publish Date
2002
Start Page
101
End Page
112

Recombinant polyclonal antibody libraries.

We describe a technology for generating recombinant polyclonal antibody libraries (PCALs) that enables the creation and perpetuation of standardized mixtures of polyclonal whole antibodies specific for a multiantigen (or polyantigen). Therefore, this technology combines the advantages of targeting multiple antigenic determinants -- high avidity, low likelihood of antigen 'escape variants', and efficient mediation of effector functions, with the advantages of using monoclonal antibodies -- unlimited supply of standardized reagents and the availability of the genetic material for desired manipulations. The technology for generating recombinant polyclonal antibody libraries begins with the creation of phage display Fab (antibody) libraries. This is followed by selection of sublibraries with desired antigen specificities, and mass transfer of the variable region gene pairs of the selected sublibraries to a mammalian expression vector for generation of libraries of polyclonal whole antibodies. We review here our experiments for selection of phage display antibody libraries against microbes and tumor cells, as well as the recent literature on the selection of phage display antibody libraries to multiantigen targets.

Authors
Sharon, J; Sarantopoulos, S; Den, W; Kao, CY; Baecher-Allan, CM; Santora, KE; Sompuram, SR; Petersen-Mahrt, S; Williams, BR
MLA Citation
Sharon, J, Sarantopoulos, S, Den, W, Kao, CY, Baecher-Allan, CM, Santora, KE, Sompuram, SR, Petersen-Mahrt, S, and Williams, BR. "Recombinant polyclonal antibody libraries." Combinatorial chemistry & high throughput screening 3.3 (June 2000): 185-196.
PMID
10903378
Source
epmc
Published In
Combinatorial Chemistry and High Throughput Screening
Volume
3
Issue
3
Publish Date
2000
Start Page
185
End Page
196
DOI
10.2174/1386207003331643

Generation of a polyclonal fab phage display library to the human breast carcinoma cell line BT-20.

We have previously described a vector system for generating recombinant polyclonal antibody libraries. This system uses bidirectional phagemid and mammalian expression vectors to facilitate mass transfer of selected variable light and variable heavy (VL-VH) region gene pairs from the phagemid to the mammalian vector, to express polyclonal libraries of whole IgG antibodies. We report here the first stage of generating a polyclonal antibody library to the human breast carcinoma cell line BT-20, using this vector system. VL and VH region gene pairs were obtained from a mouse immunized with BT-20 cells, and cloned, in opposite transcriptional orientations, in the bidirectional phagemid vector, to produce an Fab phage display library. This library was selected by panning on BT-20 cells and shown to bind specifically to BT-20 cells. Such libraries, after suitable negative selection to eliminate major reactivities against normal tissue, could be transferred in mass to our bidirectional mammalian expression vector for production of libraries of chimeric antibodies with mouse V regions and human constant (C) regions. These polyclonal antibody libraries will mediate effector functions and are expected to be useful for breast cancer therapy, as well as diagnosis.

Authors
Santora, KE; Sarantopoulos, S; Den, W; Petersen-Mahrt, S; Sompuram, SR; Sharon, J
MLA Citation
Santora, KE, Sarantopoulos, S, Den, W, Petersen-Mahrt, S, Sompuram, SR, and Sharon, J. "Generation of a polyclonal fab phage display library to the human breast carcinoma cell line BT-20." Combinatorial chemistry & high throughput screening 3.1 (February 2000): 51-57.
PMID
10702614
Source
epmc
Published In
Combinatorial Chemistry and High Throughput Screening
Volume
3
Issue
1
Publish Date
2000
Start Page
51
End Page
57
DOI
10.2174/1386207003327765

Generation of a polyclonal Fab phage display library to the protozoan parasite Cryptosporidium parvum.

We had developed a technology for creation of recombinant polyclonal antibody libraries, standardized perpetual mixtures of polyclonal whole antibodies for which the genes are available and can be altered as desired. We report here the first phase of generating a polyclonal antibody library to Cryptosporidium parvum, a protozoan parasite that causes severe disease in AIDS patients, for which there is no effective treatment. BALB/c mice, immunized by neonatal oral infection with oocysts followed by intraperitoneal immunization with a sporozoite/oocyst preparation of C. parvum, were used for construction of a Fab phage display library in a specially-designed bidirectional vector. This library was selected for reactivity to an oocyst/sporozoite preparation, and was shown to be antigen-specific and diverse. Following mass transfer of the selected variable region gene pairs to appropriate mammalian expression vectors, such anti-C. parvum Fab phage display libraries could be used to develop chimeric polyclonal antibody libraries, with mouse variable regions and human constant regions, for passive immunotherapy of C. parvum infection.

Authors
Baecher-Allan, CM; Santora, K; Sarantopoulos, S; Den, W; Sompuram, SR; Sharon, J; Cevallos, AM; Bhat, N; Ward, H
MLA Citation
Baecher-Allan, CM, Santora, K, Sarantopoulos, S, Den, W, Sompuram, SR, Sharon, J, Cevallos, AM, Bhat, N, and Ward, H. "Generation of a polyclonal Fab phage display library to the protozoan parasite Cryptosporidium parvum." Combinatorial chemistry & high throughput screening 2.6 (December 1999): 319-325.
PMID
10644857
Source
epmc
Published In
Combinatorial Chemistry and High Throughput Screening
Volume
2
Issue
6
Publish Date
1999
Start Page
319
End Page
325

A bidirectional phage display vector for the selection and mass transfer of polyclonal antibody libraries.

An approach to the creation of antigen-specific polyclonal libraries of intact antibodies is presented. A polyclonal library of Fab antibody fragments would be expressed using a phage display vector, and selected for reactivity with an antigen or group of antigens. For conversion into a sublibrary of intact polyclonal antibodies, the selected heavy (H) and light (L) chain variable (V) region gene combinations would be transferred in mass, as linked pairs, to a eukaryotic expression vector which provides immunoglobulin (Ig) constant (C) region genes. To enable this selection and transfer, a bidirectional phage display vector was generated, in which the V region gene pairs are linked head to head in opposite transcriptional orientations. The functionality of this vector was demonstrated by the selection, transfer and expression of linked V region gene pairs derived from an A/J mouse that had been immunized with p-azophenylarsonate (Ars)-coupled keyhole limpet hemocyanin (KLH). As expected, the expressed IgG2b anti-Ars antibodies with selected V region gene pairs were shown to have V region sequences and Ars-binding characteristics similar to those of anti-Ars hybridoma antibodies. The technology presented here has potential for many diagnostic and therapeutic applications. These include the generation of polyclonal antibody libraries against multiple epitopes on infectious agents or cancer cells, and of polyclonal libraries encoding chimeric molecules composed of antibody V regions and T cell receptor C regions.

Authors
Den, W; Sompuram, SR; Sarantopoulos, S; Sharon, J
MLA Citation
Den, W, Sompuram, SR, Sarantopoulos, S, and Sharon, J. "A bidirectional phage display vector for the selection and mass transfer of polyclonal antibody libraries." Journal of immunological methods 222.1-2 (January 1999): 45-57.
PMID
10022371
Source
epmc
Published In
Journal of Immunological Methods
Volume
222
Issue
1-2
Publish Date
1999
Start Page
45
End Page
57
DOI
10.1016/s0022-1759(98)00178-1

A method for linking VL and VH region genes that allows bulk transfer between vectors for use in generating polyclonal IgG libraries.

Libraries of Ab fragments have been produced by others from light and heavy chain cDNAs derived from populations of B lymphocytes and expressed in bacteria. However, such libraries have not been transferred to eukaryotic expression vectors to generate polyclonal libraries of intact glycosylated Abs that can mediate effector functions. We present a method for transferring pairs of linked VL-VH region genes between circular prokaryotic and eukaryotic vectors. The key feature of the transfer is that the VL and VH region genes are linked head to head (<-->) in opposite transcriptional orientations. To illustrate this method, a pair of VL and VH region cDNAs derived from an existing hybridoma cell line were linked head to head by PCR, transferred as a unit between vectors, and expressed as an IgG Ab with Ag binding activity. Although we tested the transfer of a single VL-VH region gene pair, this system is expected to allow the bulk transfer of physically linked VL-VH region gene combinations between different circular vectors and the expression of the same library as either Ab fragments or intact Abs.

Authors
Sarantopoulos, S; Kao, CY; Den, W; Sharon, J
MLA Citation
Sarantopoulos, S, Kao, CY, Den, W, and Sharon, J. "A method for linking VL and VH region genes that allows bulk transfer between vectors for use in generating polyclonal IgG libraries." Journal of immunology (Baltimore, Md. : 1950) 152.11 (June 1994): 5344-5351.
PMID
8189052
Source
epmc
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
152
Issue
11
Publish Date
1994
Start Page
5344
End Page
5351

Cloned endothelium derived from autoimmune vascular disease retain structural and functional characteristics of normal endothelial cells.

MRL/1pr mice demonstrate anatomic specificity in their development of vasculitis including the small- and medium-sized muscular arteries of the mesentery. To define the functional role of endothelium in vasculitis, we have cloned endothelial cells derived from inflamed small- and medium-sized arteries. Primary cells were derived by enzymatic dispersement and endothelial cells were selected by utilizing a combination of specific culture conditions. Cloned endothelium were developed utilizing limiting dilution cultures supplemented by endothelial cell growth factor. The cloned endothelial cells express many structural features of mature endothelial cells including Factor VIII-RA, non-muscle-specific actin, and Weibel-Palade bodies. Functionally, the clones express functional receptors for the scavenger pathway for LDL metabolism. The cells do not express Class I MHC antigens; however, IFN-beta and IFN-gamma stimulate Class I MHC expression after 24 h, which induces lysis of virus-infected cloned endothelium by Class I-restricted virus-primed T cells. In direct contrast to site-identical vascular smooth muscle cells (VSMCs), endothelial cells do not spontaneously express Class II MHC antigens, nor do they secrete biologically relevant levels of IL-1 unless triggered by lipopolysaccharide. The availability of site-specific cloned endothelium along with cloned VSMCs from autoimmune mice should resolve major experimental controversies involving the pathophysiology of inflammatory vascular disease.

Authors
Moyer, CF; Huggins, E; Sarantopoulos, S; Lewis, JC; Sajuthi, D; Biron, CA; Reinisch, CL
MLA Citation
Moyer, CF, Huggins, E, Sarantopoulos, S, Lewis, JC, Sajuthi, D, Biron, CA, and Reinisch, CL. "Cloned endothelium derived from autoimmune vascular disease retain structural and functional characteristics of normal endothelial cells." Experimental cell research 199.1 (March 1992): 63-73.
PMID
1735462
Source
epmc
Published In
Experimental Cell Research
Volume
199
Issue
1
Publish Date
1992
Start Page
63
End Page
73
DOI
10.1016/0014-4827(92)90462-h
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