Browsing by Author "Sarantopoulos, Stefanie"
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Item Open Access A Randomized Phase II Crossover Study of Imatinib or Rituximab for Cutaneous Sclerosis after Hematopoietic Cell Transplantation.(Clin Cancer Res, 2016-01-15) Arai, Sally; Pidala, Joseph; Pusic, Iskra; Chai, Xiaoyu; Jaglowski, Samantha; Khera, Nandita; Palmer, Jeanne; Chen, George L; Jagasia, Madan H; Mayer, Sebastian A; Wood, William A; Green, Michael; Hyun, Teresa S; Inamoto, Yoshihiro; Storer, Barry E; Miklos, David B; Shulman, Howard M; Martin, Paul J; Sarantopoulos, Stefanie; Lee, Stephanie J; Flowers, Mary EDPURPOSE: Cutaneous sclerosis occurs in 20% of patients with chronic graft-versus-host disease (GVHD) and can compromise mobility and quality of life. EXPERIMENTAL DESIGN: 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. RESULTS: 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. CONCLUSIONS: 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.Item Open Access Alphavirus Replicon Particle Vaccine Breaks B Cell Tolerance and Rapidly Induces IgG to Murine Hematolymphoid Tumor Associated Antigens.(Frontiers in immunology, 2022-01) Su, Hsuan; Imai, Kazuhiro; Jia, Wei; Li, Zhiguo; DiCioccio, Rachel A; Serody, Jonathan S; Poe, Jonathan C; Chen, Benny J; Doan, Phuong L; Sarantopoulos, StefanieDe novo immune responses to myeloid and other blood-borne tumors are notably limited and ineffective, making our ability to promote immune responses with vaccines a major challenge. While focus has been largely on cytotoxic cell-mediated tumor eradication, B-cells and the antibodies they produce also have roles in anti-tumor responses. Indeed, therapeutic antibody-mediated tumor cell killing is routinely employed in patients with hematolymphoid cancers, but whether endogenous antibody responses can be incited to blood-born tumors remains poorly studied. A major limitation of immunoglobulin therapies is that cell surface expression of tumor-associated antigen (TAA) targets is dynamic and varied, making promotion of polyclonal, endogenous B cell responses appealing. Since many TAAs are self-antigens, developing tumor vaccines that enable production of antibodies to non-polymorphic antigen targets remains a challenge. As B cell responses to RNA vaccines are known to occur, we employed the Viral Replicon Particles (VRP) which was constructed to encode mouse FLT3. The VRP-FLT3 vaccine provoked a rapid IgG B-cell response to this self-antigen in leukemia and lymphoma mouse models. In addition, IgGs to other TAAs were also produced. Our data suggest that vaccination with RNA viral particle vectors incites a loss of B-cell tolerance that enables production of anti-tumor antibodies. This proof of principle work provides impetus to employ such strategies that lead to a break in B-cell tolerance and enable production of broadly reactive anti-TAA antibodies as potential future therapeutic agents for patients with hematolymphoid cancers.Item Open Access Antibodies are back for thymic attack in cGVHD.(Blood, 2016-05-05) Sarantopoulos, StefanieItem Open Access B-cell targeting in chronic Graft-versus-Host disease.(Blood, 2018-02-01) Zeiser, Robert; Sarantopoulos, Stefanie; Blazar, Bruce ROver the last decade our understanding of the pathophysiology of chronic graft-versus-host disease (cGVHD) has improved considerably. In this spotlight, we discuss emerging insights into the pathophysiology of cGVHD with a focus on B-cells. First, we summarize supporting evidence derived from mouse and human studies. Next, novel cGVHD therapy approaches that target B-cells will be covered to provide treating physicians with an overview of the rationale behind the emerging armamentarium against cGVHD.Item Open Access Decreased Mortality in 1-Year Survivors of Umbilical Cord Blood Transplant vs. Matched Related or Matched Unrelated Donor Transplant in Patients with Hematologic Malignancies.(Transplant Cell Ther, 2021-05-12) Bohannon, Lauren; Tang, Helen; Page, Kristin; Ren, Yi; Jung, Sin-Ho; Artica, Alexandra; Britt, Anne; Islam, Prioty; Siamakpour-Reihani, Sharareh; Giri, Vinay; Lew, Meagan; Kelly, Matthew; Choi, Taewoong; Gasparetto, Cristina; Long, Gwynn; Lopez, Richard; Rizzieri, David; Sarantopoulos, Stefanie; Chao, Nelson; Horwitz, Mitchell; Sung, AnthonyBACKGROUND: Allogeneic hematopoietic stem cell transplantation (HCT) has the potential to cure hematologic malignancies, but is associated with significant morbidity and mortality. While deaths during the first year after transplant are often attributable to treatment toxicities and complications, death after the first year may be due to sequelae of accelerated aging caused by cellular senescence. Cytotoxic therapies and radiation used in cancer treatments and conditioning regimens for HCT can induce aging at the molecular level; HCT patients experience time-dependent effects, such as frailty and aging-associated diseases, more rapidly than people who have not been exposed to these treatments. Consistent with this, recipients of younger cells tend to have decreased markers of aging and improved survival, decreased GVHD, and lower relapse rates. OBJECTIVES: Given that umbilical cord blood (UCB) is the youngest donor source available, we studied the outcomes after the first year of UCB transplant vs. matched related donor (MRD) and matched unrelated donor (MUD) transplant in patients with hematologic malignancies over a 20-year period. STUDY DESIGN: In this single center, retrospective study, we examined the outcomes of all adult patients who underwent their first allogeneic HCT through the Duke Adult Bone Marrow Transplant (ABMT) program from January 1, 1996 to December 31, 2015, to allow for at least 3 years of follow-up. Patients were excluded if they died or were lost to follow-up before day 365 post-HCT; received an allogeneic HCT for a disease other than a hematologic malignancy; or received cells from a haploidentical or mismatched adult donor. RESULTS: UCB recipients experienced a better unadjusted overall survival than MRD/MUD recipients (log rank p=0.03, Figure 1, median OS: UCB not reached, MRD/MUD 7.4 years). After adjusting for selected covariates, UCB recipients who survived at least 1 year after HCT had a hazard of death that was 31% lower than that of MRD/MUD recipients (HR: 0.69, 95% CI: 0.47-0.99, p=0.049). This trend held true in a subset analysis of subjects with acute leukemia. UCB recipients also experienced lower rates of moderate or severe chronic graft-versus-host disease (GVHD) and non-relapse mortality, and slower time to relapse. UCB and MRD/MUD recipients experienced similar rates of grade 2-4 acute GVHD, chronic GHVD, secondary malignancy, and subsequent allogeneic HCT. CONCLUSIONS: UCB is already widely used as a donor source in pediatric HCT; however, adult outcomes and adoption have historically lagged behind in comparison. Recent advancements in UCB transplantation such as the implementation of lower-intensity conditioning regimens, double unit transplants, and ex-vivo expansion have improved early mortality, making UCB an increasingly attractive donor source for adults; furthermore, our findings suggest that UCB may actually be a preferred donor source for mitigating late effects of HCT.Item Open Access Heightened TLR7 signaling primes BCR-activated B cells in chronic graft-versus-host disease for effector functions.(Blood advances, 2024-02) Bracken, Sonali J; Suthers, Amy N; DiCioccio, Rachel A; Su, Hsuan; Anand, Sarah; Poe, Jonathan C; Jia, Wei; Visentin, Jonathan; Basher, Fahmin; Jordan, Collin Z; McManigle, William C; Li, Zhiguo; Hakim, Frances T; Pavletic, Steven Z; Bhuiya, Nazmim S; Ho, Vincent T; Horwitz, Mitchell E; Chao, Nelson J; Sarantopoulos, StefanieAbstract
Chronic graft-versus-host disease (cGVHD) is a debilitating, autoimmune-like syndrome that can occur after allogeneic hematopoietic stem cell transplantation. Constitutively activated B cells contribute to ongoing alloreactivity and autoreactivity in patients with cGVHD. Excessive tissue damage that occurs after transplantation exposes B cells to nucleic acids in the extracellular environment. Recognition of endogenous nucleic acids within B cells can promote pathogenic B-cell activation. Therefore, we hypothesized that cGVHD B cells aberrantly signal through RNA and DNA sensors such as Toll-like receptor 7 (TLR7) and TLR9. We found that B cells from patients and mice with cGVHD had higher expression of TLR7 than non-cGVHD B cells. Using ex vivo assays, we found that B cells from patients with cGVHD also demonstrated increased interleukin-6 production after TLR7 stimulation with R848. Low-dose B-cell receptor (BCR) stimulation augmented B-cell responses to TLR7 activation. TLR7 hyperresponsiveness in cGVHD B cells correlated with increased expression and activation of the downstream transcription factor interferon regulatory factor 5. Because RNA-containing immune complexes can activate B cells through TLR7, we used a protein microarray to identify RNA-containing antigen targets of potential pathological relevance in cGVHD. We found that many of the unique targets of active cGVHD immunoglobulin G (IgG) were nucleic acid-binding proteins. This unbiased assay identified the autoantigen and known cGVHD target Ro-52, and we found that RNA was required for IgG binding to Ro-52. Herein, we find that BCR-activated B cells have aberrant TLR7 signaling responses that promote potential effector responses in cGVHD.Item Open Access Impaired bone marrow B-cell development in mice with a bronchiolitis obliterans model of cGVHD.(Blood advances, 2018-09-18) Kolupaev, Oleg V; Dant, Trisha A; Bommiasamy, Hemamalini; Bruce, Danny W; Fowler, Kenneth A; Tilley, Stephen L; McKinnon, Karen P; Sarantopoulos, Stefanie; Blazar, Bruce R; Coghill, James M; Serody, Jonathan SChronic graft-versus-host disease (cGVHD) causes significant morbidity and mortality in patients after allogeneic bone marrow (BM) or stem cell transplantation (allo-SCT). Recent work has indicated that both T and B lymphocytes play an important role in the pathophysiology of cGVHD. Previously, our group showed a critical role for the germinal center response in the function of B cells using a bronchiolitis obliterans (BO) model of cGVHD. Here, we demonstrated for the first time that cGVHD is associated with severe defects in the generation of BM B lymphoid and uncommitted common lymphoid progenitor cells. We found an increase in the number of donor CD4+ T cells in the BM of mice with cGVHD that was negatively correlated with B-cell development and the frequency of osteoblasts and Prrx-1-expressing perivascular stromal cells, which are present in the B-cell niche. Use of anti-DR3 monoclonal antibodies to enhance the number of donor regulatory T cells (Tregs) in the donor T-cell inoculum ameliorated the pathology associated with BO in this model. This correlated with an increased number of endosteal osteoblastic cells and significantly improved the generation of B-cell precursors in the BM after allo-SCT. Our work indicates that donor Tregs play a critical role in preserving the generation of B-cell precursors in the BM after allo-SCT. Approaches to enhance the number and/or function of donor Tregs that do not enhance conventional T-cell activity may be important to decrease the incidence and severity of cGVHD in part through normal B-cell lymphopoiesis.Item Open Access Morphologic leukemia-free state in acute myeloid leukemia is sufficient for successful allogeneic hematopoietic stem cell transplant.(Blood cancer journal, 2021-05-16) Pabon, Cindy M; Li, Zhiguo; Hennig, Therese; de Castro, Carlos; Neff, Jadee L; Horwitz, Mitchell E; LeBlanc, Thomas W; Long, Gwynn D; Lopez, Richard D; Sung, Anthony D; Chao, Nelson; Gasparetto, Cristina; Sarantopoulos, Stefanie; Adams, Donna B; Erba, Harry; Rizzieri, David AItem Open Access Notch signaling mediated by Delta-like1/4 ligands controls the pathogenesis of chronic graft-versus-host disease in mice.(Blood, 2018-09-04) Radojcic, Vedran; Paz, Katelyn; Chung, Jooho; Du, Jing; Perkey, Eric T; Flynn, Ryan; Ivcevic, Sanja; Zaiken, Michael; Friedman, Ann; Yan, Minhong; Pletneva, Maria A; Sarantopoulos, Stefanie; Siebel, Christian W; Blazar, Bruce R; Maillard, IvanChronic GVHD (cGVHD) is a major complication of allogeneic hematopoietic cell transplantation (allo-HCT) and remains an area of unmet clinical need with few treatment options available. Notch blockade prevents acute GVHD in multiple mouse models, but the impact of Notch signaling on cGVHD remains unknown. Using genetic and antibody-mediated strategies of Notch inhibition, we investigated the role of Notch signaling in complementary mouse cGVHD models that mimic several aspects of human cGVHD in search of candidate therapeutics. In the B10.D2→BALB/c model of sclerodermatous cGVHD, Delta-like4 (Dll4)-driven Notch signaling was essential for disease development. Antibody-mediated Dll4 inhibition conferred maximum benefits when pursued early in a preventative fashion, with anti-Delta-like1 (Dll1) enhancing early protection. Notch-deficient alloantigen-specific T cells showed no early defects in proliferation or helper polarization in vivo, but subsequently exhibited markedly decreased cytokine secretion and enhanced accumulation of FoxP3+ regulatory T cells. In the B6→B10.BR MHC-mismatched model with multi-organ system cGVHD and prominent bronchiolitis obliterans (BO) but not skin manifestations, absence of Notch signaling in T cells provided long-lasting disease protection that was replicated by systemic targeting of Dll1, Dll4, or both Notch ligands even during established disease. Notch inhibition decreased target organ damage and germinal center formation. Moreover, decreased BO-cGVHD was observed upon inactivation of Notch1 and/or Notch2 in T cells. Systemic targeting of Notch2 alone was safe and conferred therapeutic benefits. Altogether, Notch ligands and receptors regulate key pathogenic steps in cGVHD and emerge as novel druggable targets to prevent or treat different forms of cGVHD.Item Open Access Plerixafor (a CXCR4 antagonist) following myeloablative allogeneic hematopoietic stem cell transplantation enhances hematopoietic recovery.(J Hematol Oncol, 2018-03-04) Green, Michael MB; Chao, Nelson; Chhabra, Saurabh; Corbet, Kelly; Gasparetto, Cristina; Horwitz, Ari; Li, Zhiguo; Venkata, Jagadish Kummetha; Long, Gwynn; Mims, Alice; Rizzieri, David; Sarantopoulos, Stefanie; Stuart, Robert; Sung, Anthony D; Sullivan, Keith M; Costa, Luciano; Horwitz, Mitchell; Kang, YubinBACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. TRIAL REGISTRATION: ClinicalTrials.gov NCT01280955.Item Open Access Rad18 confers hematopoietic progenitor cell DNA damage tolerance independently of the Fanconi Anemia pathway in vivo.(Nucleic Acids Res, 2016-05-19) Yang, Yang; Poe, Jonathan C; Yang, Lisong; Fedoriw, Andrew; Desai, Siddhi; Magnuson, Terry; Li, Zhiguo; Fedoriw, Yuri; Araki, Kimi; Gao, Yanzhe; Tateishi, Satoshi; Sarantopoulos, Stefanie; Vaziri, CyrusIn 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.Item Open Access Review: Hematopoietic Stem Cell Transplantation for Scleroderma: Effective Immunomodulatory Therapy for Patients With Pulmonary Involvement.(Arthritis Rheumatol, 2016-10) Sullivan, Keith M; Shah, Ankoor; Sarantopoulos, Stefanie; Furst, Daniel EItem Open Access Single-cell landscape analysis unravels molecular programming of the human B cell compartment in chronic GVHD.(JCI insight, 2023-06) Poe, Jonathan C; Fang, Jiyuan; Zhang, Dadong; Lee, Marissa R; DiCioccio, Rachel A; Su, Hsuan; Qin, Xiaodi; Zhang, Jennifer Y; Visentin, Jonathan; Bracken, Sonali J; Ho, Vincent T; Wang, Kathy S; Rose, Jeremy J; Pavletic, Steven Z; Hakim, Frances T; Jia, Wei; Suthers, Amy N; Curry-Chisolm, Itaevia M; Horwitz, Mitchell E; Rizzieri, David A; McManigle, William C; Chao, Nelson J; Cardones, Adela R; Xie, Jichun; Owzar, Kouros; Sarantopoulos, StefanieAlloreactivity can drive autoimmune syndromes. After allogeneic hematopoietic stem cell transplantation (allo-HCT), chronic graft-versus-host disease (cGVHD), a B cell-associated autoimmune-like syndrome, commonly occurs. Because donor-derived B cells continually develop under selective pressure from host alloantigens, aberrant B cell receptor (BCR) activation and IgG production can emerge and contribute to cGVHD pathobiology. To better understand molecular programing of B cells in allo-HCT, we performed scRNA-Seq analysis on high numbers of purified B cells from patients. An unsupervised analysis revealed 10 clusters, distinguishable by signature genes for maturation, activation, and memory. Within the memory B cell compartment, we found striking transcriptional differences in allo-HCT patients compared with healthy or infected individuals, including potentially pathogenic atypical B cells (ABCs) that were expanded in active cGVHD. To identify intrinsic alterations in potentially pathological B cells, we interrogated all clusters for differentially expressed genes (DEGs) in active cGVHD versus patients who never had signs of immune tolerance loss (no cGVHD). Active cGVHD DEGs occurred in both naive and BCR-activated B cell clusters. Remarkably, some DEGs occurred across most clusters, suggesting common molecular programs that may promote B cell plasticity. Our study of human allo-HCT and cGVHD provides understanding of altered B cell memory during chronic alloantigen stimulation.Item Open Access Systemic Sclerosis as an Indication for Autologous Hematopoietic Cell Transplantation: Position Statement from the American Society for Blood and Marrow Transplantation.(Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, 2018-06-25) Sullivan, Keith M; Majhail, Navneet S; Bredeson, Christopher; Carpenter, Paul A; Chatterjee, Soumya; Crofford, Leslie J; Georges, George E; Nash, Richard A; Pasquini, Marcelo C; Sarantopoulos, Stefanie; Storek, Jan; Savani, Bipin; St Clair, E WilliamSystemic sclerosis is a progressive inflammatory disease that is frequently fatal and has limited treatment options. High-dose chemotherapy with autologous hematopoietic cell transplantation (AHCT) has been evaluated as treatment for this disease in observational studies, multicenter randomized controlled clinical trials, and meta-analyses. On behalf of the American Society for Blood and Marrow Transplantation (ASBMT), a panel of experts in transplantation and rheumatology was convened to review available evidence and make a recommendation on AHCT as an indication for systemic sclerosis. Three randomized trials have compared the efficacy of AHCT with cyclophosphamide only, and all demonstrated benefit for the AHCT arm for their primary endpoint (improvement in the American Scleroderma Stem Cell versus Immune Suppression Trial, event-free survival in Autologous Stem Cell Transplantation International Scleroderma trial, and change in global rank composite score in Scleroderma: Cyclophosphamide or Transplantation trial). AHCT recipients also had better overall survival and a lower rate of disease progression. These findings have been confirmed in subsequent meta-analyses. Based on this high-quality evidence, the ASBMT recommends systemic sclerosis should be considered as a "standard of care" indication for AHCT. Close collaboration between rheumatologists and transplant clinicians is critical for optimizing patient selection and patient outcomes. Transplant centers in the United States are strongly encouraged to report patient and outcomes data to the Center for International Blood and Marrow Transplant Research on their patients receiving AHCT for this indication.