Stephan A Grupp

The Children's Hospital of Philadelphia, Filadelfia, Pennsylvania, United States

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Publications (123)908.1 Total impact

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    ABSTRACT: Early T-cell precursor (ETP) acute lymphoblastic leukemia (ALL) is a recently described subtype of T-ALL characterized by a unique immunophenotype and genomic profile as well as a high rate of induction failure. Frequent mutations in cytokine receptor and JAK/STAT signaling pathways led us to hypothesize that ETP-ALL is dependent on JAK/STAT signaling. Here we demonstrate aberrant activation of the JAK/STAT pathway in ETP-ALL blasts relative to non-ETP T-ALL. Moreover, ETP-ALL showed hyperactivation of STAT5 in response to IL7, an effect that was abrogated by the JAK1/2 inhibitor ruxolitinib. In vivo, ruxolitinib displayed activity in 6/6 patient-derived murine xenograft models of ETP-ALL, with profound single-agent efficacy in 5 models. Ruxolitinib treatment decreased peripheral blast counts relative to pre-treatment levels and compared to control (P<0.01) in 5/6 ETP-ALL xenografts, with marked reduction in mean splenic blast counts (P<0.01) in 6/6 samples. Surprisingly, both JAK/STAT pathway activation and ruxolitinib efficacy were independent of the presence of JAK/STAT pathway mutations, raising the possibility that the therapeutic potential of ruxolitinib in ETP-ALL extends beyond those cases with JAK mutations. These findings establish the preclinical in vivo efficacy of ruxolitinib in ETP-ALL, a biologically distinct subtype for which novel therapies are needed. Copyright © 2015 American Society of Hematology.
    Blood 02/2015; 125(11). DOI:10.1182/blood-2014-06-580480 · 9.78 Impact Factor
  • Nathan Singh, David M Barrett, Stephan A Grupp
    OncoImmunology 01/2015; 3(12):e962974. DOI:10.4161/21624011.2014.962974 · 6.28 Impact Factor
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    ABSTRACT: Relapsed and refractory leukemias pose substantial challenges in both children and adults, with very little progress being made in more than a decade. Targeted immunotherapy using chimeric antigen receptor (CAR)-modified T cells has emerged as a potent therapy with an innovative mechanism. Dramatic clinical responses with complete remission rates as high as 90% have been reported using CAR-modified T cells directed against the B-cell-specific antigen CD19 in patients with relapsed/refractory acute lymphoblastic leukemia. Supraphysiologic T-cell proliferation, a hallmark of this therapy, contributes to both efficacy and the most notable toxicity, cytokine release syndrome, posing a unique challenge for toxicity management. Further studies are necessary to identify additional targets, standardize approaches to cytokine release syndrome management, and determine the durability of remissions. © 2014 by The American Society of Hematology. All rights reserved.
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    ABSTRACT: Relapsed acute lymphoblastic leukemia (ALL) is difficult to treat despite the availability of aggressive therapies. Chimeric antigen receptor-modified T cells targeting CD19 may overcome many limitations of conventional therapies and induce remission in patients with refractory disease.
    New England Journal of Medicine 10/2014; 371(16):1507-17. DOI:10.1056/NEJMoa1407222 · 54.42 Impact Factor
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    ABSTRACT: Idiopathic pneumonia syndrome (IPS) is an acute, non-infectious lung disorder associated with high morbidity and mortality following hematopoietic cell transplantation. Previous studies have suggested a role for TNFα in the pathogenesis of IPS. We report a multi-center phase II trial investigating a soluble TNF binding protein, etanercept (Enbrel(®), Amgen) for the treatment of pediatric patients with IPS. Eligible patients were <18 years, within 120 days post-transplant, with radiographic evidence of a diffuse pneumonitis. All patients underwent a pre-therapy broncho-alveolor lavage (BAL) to establish the diagnosis of IPS. Systemic corticosteroids (2.0 mg/kg/day) plus etanercept (0.4 mg/kg twice weekly x 8 doses) were administered. Response was defined as survival and discontinuation of supplemental oxygen support by day 28 of study. Thirty-nine patients (median age 11y, range 1-17y) were enrolled, with 11 of 39 patients non-evaluable due to identification of pathogens from their pre-therapy BAL. In the remaining 28 patients, the median FiO2 at study entry was 45%, with 17 of 28 requiring mechanical ventilation. Complete responses were seen in 20 (71%) patients, with a median time to response 10 days (range 1-24). Response rates were higher for patients not requiring mechanical ventilation at study entry (100% vs. 53%,p=0.01). Overall survival at 28 days and 1-year post-therapy were 89% (95% CI:70-96) and 63% (95% CI:42-79) respectively. Plasma levels of pro-inflammatory cytokines were significantly increased at onset of therapy, subsequently decreasing in responding patients. The addition of etanercept to high dose corticosteroids was associated with high response rates and survival in children with IPS.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 09/2014; 21(1). DOI:10.1016/j.bbmt.2014.09.019 · 3.15 Impact Factor
  • Stephan A Grupp
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    ABSTRACT: CD19-directed chimeric antigen receptor T cells (CART19 or CTL019) have been used with success in pediatric and adult acute lymphocytic leukemia (ALL) and chronic lymphocytic leukemia (CLL) patients. While this therapy has caused toxicities, including cytokine release syndrome and macrophage activation syndrome, these conditions are reversible with IL-6 blockade using the monoclonal antibody tocilizumab. Furthermore, 90% of the very high-risk patients who underwent infusion with CTL019 achieved a complete response, despite the fact that they previously failed multiple therapies and/or transplant. With improved cell persistence, this immunotherapy may one day prove to be more than a bridge to transplant and may in fact be a transplant alternative. Copyright © 2014 Elsevier Ltd. All rights reserved.
    Bailli&egrave re s Best Practice and Research in Clinical Haematology 09/2014; 27(3-4):222-228. DOI:10.1016/j.beha.2014.10.014 · 2.55 Impact Factor
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    ABSTRACT: Chimeric antigen receptor (CAR) therapy has begun to demonstrate success as a novel treatment modality for hematologic malignancies. The success observed thus far has been with T cells permanently-engineered to express chimeric receptors. T cells engineered using RNA electroporation represent an alternative with the potential for similar efficacy and greater safety when initially targeting novel antigens. Neuroblastoma is a common pediatric solid tumor with the potential to be targeted using immunotherapy. We performed xenograft studies in NSG mice assessing the efficacy of both permanently-modified and transiently-modified CAR T cells directed against the neuroblastoma antigen GD2 in both local and disseminated disease models. Disease response was monitored by tumor volume measurement and histological examination, as well as in vivo bioluminescence. RNA-modified GD2 CAR T cells mediated rapid tumor destruction when delivered locally. A single infusion of lentivirally-modified GD2 CAR T cells resulted in long-term control of disseminated disease. Multiple infusions of RNA GD2 CAR T cells slowed progression of disseminated disease and improved survival, but did not result in long-term disease control. Histologic examination revealed that the transiently-modified cells were unable to significantly penetrate the tumor environment when delivered systemically, despite multiple CAR T cell infusions. Thus, we demonstrate that RNA-modified GD2 CAR T cells can mediate effective anti-tumor responses in vivo, and permanently-modified cells are able to control disseminated neuroblastoma in xenograft mice. Lack of long-term disease control by RNA-engineered cells resulted from an inability to penetrate the tumor microenvironment.
    08/2014; DOI:10.1158/2326-6066.CIR-14-0051
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    ABSTRACT: Although allogeneic hematopoietic stem-cell transplantation (HSCT) is a curative approach for many pediatric patients with hematologic malignancies and some non-malignant disorders, there are still critical obstacles to overcome including relapse, engraftment failure, graft-versus-host disease (GvHD) and infection. Harnessing the immune system to induce a graft-versus-tumor (GvT) effect or rapidly restore anti-viral immunity through the use of donor lymphocyte infusion (DLI) has been remarkably successful in some settings. Unfortunately, the responses to DLI can be variable and GVHD is common. Hence, manipulations to minimize GVHD while restoring antiviral immunity and enhancing GvT are necessary to improve outcomes after allogeneic HSCT. Cellular therapies are defined as treatment modalities in which hematopoietic or non-hematopoietic cells are used as therapeutic agents and offer this promise to improve outcomes post HSCT. This review will present an overview of the field for pediatric cell therapies in the transplant setting and discuss how we can broaden applicability beyond phase I.
    Biology of Blood and Marrow Transplantation 07/2014; 21(3). DOI:10.1016/j.bbmt.2014.07.018 · 3.35 Impact Factor
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    ABSTRACT: Grade II-IV acute graft-vs.-host disease (GVHD) occurs in approximately 35% of matched, related donor (MRD) allogeneic hematopoietic cell transplantation (HCT) recipients. We sought to determine if the combination of tacrolimus and sirolimus (Tac/Sir) was more effective than tacrolimus and methotrexate (Tac/Mtx) in preventing acute GVHD and early mortality after allogeneic MRD HCT in a phase 3, multicenter trial. The primary endpoint of the trial was to compare 114 day grade II-IV acute GVHD-free survival using an intention-to-treat analysis of 304 randomized subjects. There was no difference in the probability of day 114 grade II-IV acute GVHD-free survival (67% vs. 62%, p=0.38). Grade II-IV GVHD was similar in the Tac/Sir and Tac/Mtx arms (26% vs. 34%, p=0.48). Neutrophil and platelet engraftment were more rapid in the Tac/Sir arm (14 vs. 16 days, p<0.001; 16 vs. 19 days, p=0.03). Oropharyngeal mucositis was less severe in Tac/Sir arm (peak OMAS score 0.70 vs. 0.96, p<0.001), but otherwise toxicity was similar. Chronic GVHD, relapse-free survival and overall survival at 2 years were no different between study arms (53% vs. 45%, p=0.06; 53% vs. 54%, p=0.77; 59% vs. 63%, p=0.36). Based on similar long-term outcomes, more rapid engraftment and less oropharyngeal mucositis, the combination of Tac/Sir is an acceptable alternative to Tac/Mtx after MRD HCT. (Funded by the National Heart, Lung, and Blood Institute and National Cancer Institute; ClinicalTrials.gov number, NCT00406393).
    Blood 06/2014; 124(8). DOI:10.1182/blood-2014-04-567164 · 9.78 Impact Factor
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    ABSTRACT: It is now well established that the immune system can control and eliminate cancer cells. Adoptive T cell transfer has the potential to overcome the significant limitations associated with vaccine-based strategies in patients who are often immune compromised. Application of the emerging discipline of synthetic biology to cancer, which combines elements of genetic engineering and molecular biology to create new biological structures with enhanced functionalities, is the subject of this focused research review.
    Cancer Immunology and Immunotherapy 06/2014; DOI:10.1007/s00262-014-1568-1 · 3.94 Impact Factor
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    ABSTRACT: As immune based therapies for cancer become potent, more effective and more widely available, optimal management of their unique toxicities becomes increasingly important. Cytokine release syndrome (CRS) is a potentially life threatening toxicity that has been observed following administration of natural and bi-specific antibodies and more recently, following adoptive T cell therapies for cancer. CRS is associated with elevated circulating levels of several cytokines including IL-6 and IFNγ, and uncontrolled studies demonstrate that immunosuppression using tocilizumab, an anti-IL6R antibody, with or without corticosteroids, can reverse the syndrome. However because early and aggressive immunosuppression could limit the efficacy of the immunotherapy, current approaches seek to limit administration of immunosuppressive therapy to patients at risk for life threatening consequences of the syndrome. This report presents a novel system to grade the severity of CRS in individual patients, and a treatment algorithm for management of CRS based upon severity. The goal of our approach is to maximize the chance for therapeutic benefit from the immunotherapy while minimizing the risk for life threatening complications of CRS.
    Blood 05/2014; 124(2). DOI:10.1182/blood-2014-05-552729 · 9.78 Impact Factor
  • Cytotherapy 04/2014; 16(4):S8. DOI:10.1016/j.jcyt.2014.01.017 · 3.06 Impact Factor
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    ABSTRACT: Many patients with acute myeloid leukemia (AML) are incurable with chemotherapy and may benefit from novel approaches. One such approach involves the transfer of T cells engineered to express chimeric antigen receptors (CARs) for a specific cell surface antigen. This strategy depends upon preferential expression of the target on tumor cells. To date, the lack of AML-specific surface markers has impeded development of such CAR-based approaches. CD123, the transmembrane alpha chain of the interleukin-3 receptor, is expressed on the majority of AML but is also expressed on many normal hematopoietic cells. Here we show that CD123 is a good target for AML-directed CAR therapy, as its expression increases over time in vivo even in initially CD123(dim) populations, and that human CD123-redirected T cells (CART123) eradicate primary AML in immunodeficient mice. CART123 also eradicated normal human myelopoiesis, a surprising finding since anti-CD123 antibody-based strategies have been reportedly well-tolerated. As AML is likely preceded by clonal evolution in "pre-leukemic" hematopoietic stem cells, our observations support CART123 as a viable AML therapy, suggest that CART123-based myeloablation may be used as a novel conditioning regimen for hematopoietic cell transplantation, and raise concerns for the use of CART123 without such a rescue strategy.
    Blood 03/2014; DOI:10.1182/blood-2013-09-529537 · 9.78 Impact Factor
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    ABSTRACT: T cells redirected to specific antigen targets with engineered chimeric antigen receptors (CARs) are emerging as powerful therapies in hematologic malignancies. Various CAR designs, manufacturing processes, and study populations, among other variables, have been tested and reported in over 10 clinical trials. Here we review and compare the results of the reported clinical trials, and discuss the progress and key emerging factors that may play a role in effecting tumor responses. We also discuss the outlook for CAR T cell therapies, including managing toxicities and expanding the availability of personalized cell therapy as a promising approach to all hematologic malignancies. Many questions remain in the field of CAR T cells directed to hematologic malignancies, but the encouraging response rates pave a wide road for future investigation.
    Blood 02/2014; 123(17). DOI:10.1182/blood-2013-11-492231 · 9.78 Impact Factor
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    ABSTRACT: Sirolimus, an mTOR inhibitor, has activity against human ALL in xenograft models and efficacy in preventing acute GVHD (aGVHD). We tested whether addition of sirolimus to GVHD prophylaxis of children undergoing transplantation for ALL would decrease aGVHD and relapse, thus improving survival. Patients were randomized to tacrolimus/methotrexate (standard) or tacrolimus/methotrexate/sirolimus (experimental). The study met futility rules for survival after enrolling 146 of 259 planned patients. The proportion of patients with Grade II-IV aGVHD was 31% vs. 18% in the standard vs. the experimental arm (p=0.04), however, grade III-IV aGVHD was not statistically different (13% vs. 10%, p=0.28). Rates of veno-occlusive disease and thrombotic microangiopathy were lower in the non-sirolimus arm (9% vs. 21% VOD, p=0.05; 1% vs. 10% TMA, p=0.06). At 2 years, EFS and OS were 56% vs 46%, and 65% vs 55% in the standard and experimental arms, respectively (p= 0.28 and 0.23). Multivariate analysis showed increased relapse risk in children with ≥0.1% MRD pre-transplant, and decreased risk in patients with grades I-III aGVHD (p=0.04). Grades I-III aGVHD were associated with improved EFS (p=0.02), while grade IV aGVHD and extramedullary disease at initial diagnosis led to inferior OS. Although addition of sirolimus decreased aGVHD, survival was not improved. The study is registered with ClinicalTrials.gov (ClinicalTrials.gov Identifier: NCT00382109).
    Blood 02/2014; DOI:10.1182/blood-2013-10-534297 · 9.78 Impact Factor
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    ABSTRACT: Cytotoxic T lymphocytes modified with chimeric antigen receptors (CARs) for adoptive immunotherapy of hematologic malignancies are effective in pre-clinical models, and this efficacy has translated to success in several clinical trials. Many early trials were disappointing in large part because of the lack of proliferation and subsequent persistence of transferred cells. Recent investigations have pointed to the importance of delivering highly proliferative cells, whether of naive or early memory phenotypes. We investigated the influence of two common cell culturing methods used in early trials and their relationship to T-cell phenotype and pre-clinical efficacy. We observed that stimulation with soluble anti-CD3 antibody OKT-3 and high-dose interleukin-2 produces more effector memory-type T cells with shorter average telomeres when compared with cells generated with the use of CD3/CD28 beads. When used in xenograft models of leukemia, bead-stimulated cells proliferated earlier and to a higher degree than those generated with the use of OKT-3/IL2 and resulted in better disease control despite no difference in distribution or migration throughout the mouse. Inclusion of the known successful clinical 4-1BB endodomain in the CAR could not rescue the function of OKT-3/IL-2-cultured cells. T cells isolated from animals that survived long-term (>120 days) retained a central memory-like phenotype and demonstrated a memory response to a large re-challenge of CD19-positive leukemia. In summary, we confirm that cells with a younger phenotype or higher proliferative capacity perform better in pre-clinical models and that cell culturing influences cell phenotype seemingly independent of the 4-1BB endodomain in the CAR structure.
    Cytotherapy 01/2014; DOI:10.1016/j.jcyt.2013.10.013 · 3.06 Impact Factor
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    ABSTRACT: Chimeric antigen receptor (CAR)-modified T cells and bispecific T cell-engaging antibodies have demonstrated dramatic clinical responses in recent clinical trials. The hallmark of these novel highly active immunotherapies is nonphysiologic T cell activation, which has correlated not only with greatly increased efficacy but also with notable toxicity in some cases. We and others have observed a cytokine release syndrome (CRS), which correlates with both toxicity and efficacy in patients receiving T cell-engaging therapies. In addition to elevations in effector cytokines, such as interferon-γ, cytokines associated with hemophagocytic lymphohistiocytosis or macrophage activation syndrome, such as interleukin (IL)-10 and IL-6, may also be markedly elevated. Whereas corticosteroids may control some of these toxicities, their potential to block T cell activation and abrogate clinical benefit is a concern. Detailed studies of T cell proliferation and the resultant immune activation produced by these novel therapies have led to more targeted approaches that have the potential to provide superior toxicity control without compromising efficacy. One approach we have developed targets IL-6, a prominent cytokine in CRS, using the IL-6R antagonist tocilizumab. We will review the pathophysiology and management options for CRS associated with T cell-engaging therapies.
    The Cancer Journal 01/2014; 20(2):119-22. DOI:10.1097/PPO.0000000000000035 · 3.61 Impact Factor
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    ABSTRACT: Invariant natural killer T (iNKT) cells comprise a lineage of CD1d-restricted glycolipid-reactive T lymphocytes with important roles in host immunity to cancer. iNKT cells indirectly participate in antitumor responses by inducing dendritic cell maturation and producing cytokines that promote tumor clearance by CD8(+) T and NK cells. Although iNKT cells thereby act as potent cellular adjuvants, it is less clear whether they directly control the growth of tumors. To gain insights into the direct contribution of iNKT cells to tumor immune surveillance, we developed in vitro and in vivo systems to selectively examine the antitumor activity of iNKT cells in the absence of other cytolytic effectors. Using the EL4 T-lymphoma cell line as a model, we find that iNKT cells exert robust and specific lysis of tumor cells in vitro in a manner that is differentially-induced by iNKT cell agonists of varying TCR affinities, such as OCH, α-galactosyl ceramide and PBS44. In vitro blockade of CD1d-mediated lipid antigen presentation, disruption of T cell receptor (TCR) signaling, or loss of perforin expression significantly reduce iNKT cell killing. Consistent with these findings, iNKT cell reconstitution of T, B, and NK cell-deficient mice slows EL4 growth in vivo via TCR-CD1d and perforin-dependent mechanisms. Together, these observations establish that iNKT cells are sufficient to control the growth of T-lymphoma in vitro and in vivo. They also suggest that the induction of iNKT cell cytotoxic responses in situ might serve as a more effective strategy to prevent and/or treat CD1d(+) cancers, such as T-lymphoma.
    01/2014; 2(1):59-69. DOI:10.1158/2326-6066.CIR-13-0104
  • David M Barrett, David T Teachey, Stephan A Grupp
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    ABSTRACT: Recent clinical trials using T-cell engaging immunotherapies such as bispecific antibodies which target T cells and tumor cells, as well as engineered T cells that express targeting and activation molecules known as chimeric antigen receptors, have demonstrated powerful proof of concept. These therapies result in a significant degree of immune activation in the patient, which has correlated with greatly increased efficacy but also with notable toxicity. These therapies produce nonphysiologic T-cell activation, which is the hallmark of these new, highly active treatments. We and others have noted cytokine activation profiles that correlate with both toxicity and efficacy in patients receiving T-cell engaging therapies. Effector cytokines such as interferon-γ are elevated, but so are cytokines that are associated with macrophage activation syndrome/hemophagocytic lymphohistiocytosis, such as interleukin (IL)-10 and IL-6. Although corticosteroids can control some of these toxicities, a targeted approach may produce superior toxicity control without interfering with efficacy. One approach we have developed targets IL-6, a key cytokine in the toxicity response, using the IL-6 receptor antagonist tocilizumab. Detailed studies of the T-cell activation produced by these novel therapies has led to more targeted approaches that have the potential to control toxicity while maintaining efficacy.
    Current opinion in pediatrics 12/2013; 26(1). DOI:10.1097/MOP.0000000000000043 · 2.74 Impact Factor
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    ABSTRACT: Improved outcomes for patients with cancer hinge on the development of new targeted therapies with acceptable short-term and long-term toxicity. Progress in basic, preclinical, and clinical arenas spanning cellular immunology, synthetic biology, and cell-processing technologies has paved the way for clinical applications of chimeric antigen receptor-based therapies. This new form of targeted immunotherapy merges the exquisite targeting specificity of monoclonal antibodies with the potent cytotoxicity and long-term persistence provided by cytotoxic T cells. Although this field is still in its infancy, clinical trials have already shown clinically significant antitumor activity in neuroblastoma, chronic lymphocytic leukemia, and B cell lymphoma, and trials targeting a variety of other adult and pediatric malignancies are under way. Ongoing work is focused on identifying optimal tumor targets and on elucidating and manipulating both cell- and host-associated factors to support expansion and persistence of the genetically engineered cells in vivo. The potential to target essentially any tumor-associated cell-surface antigen for which a monoclonal antibody can be made opens up an entirely new arena for targeted therapy of cancer. Expected final online publication date for the Annual Review of Medicine Volume 65 is January 14, 2014. Please see http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates.
    Annual review of medicine 11/2013; 65. DOI:10.1146/annurev-med-060512-150254 · 9.94 Impact Factor

Publication Stats

3k Citations
908.10 Total Impact Points

Institutions

  • 1998–2015
    • The Children's Hospital of Philadelphia
      • • Division of Oncology
      • • Department of Pathology and Laboratory Medicine
      • • Department of Pediatrics
      Filadelfia, Pennsylvania, United States
  • 2013
    • University of Pennsylvania
      • "Abramson" Cancer Center
      Filadelfia, Pennsylvania, United States
  • 2003–2013
    • William Penn University
      Filadelfia, Pennsylvania, United States
  • 2010
    • National Institute of Allergy and Infectious Diseases
      Maryland, United States
  • 2000–2006
    • Dana-Farber Cancer Institute
      • Department of Pediatric Oncology
      Boston, MA, United States
  • 1994–1995
    • Brigham and Women's Hospital
      • Department of Pathology
      Boston, MA, United States