Amy B Heimberger

University of Texas MD Anderson Cancer Center, Houston, Texas, United States

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Publications (86)472.43 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: The role of tumor-induced immune modulation in cancer progression is currently a focus of investigation. The signal transducer and activator of transcription 3 (STAT3) is an established molecular hub of immunosuppression, and its signaling pathways are classically overactivated within malignancies. This article will review STAT3 operational mechanisms within the immune system and the tumor microenvironment, with a focus on therapeutic strategies that may impact outcomes for patients with cancer.
    Journal of Neuro-Oncology 02/2015; · 3.12 Impact Factor
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    ABSTRACT: The epidermal growth factor receptor variant III deletion mutation, EGFRvIII, is expressed in ∼30% of primary glioblastoma and linked to poor long-term survival. Rindopepimut consists of the unique EGFRvIII peptide sequence conjugated to keyhole limpet hemocyanin. In previous phase II trials (ACTIVATE/ACT II), rindopepimut was well tolerated with robust EGFRvIII-specific immune responses and promising progression-free and overall survival. This multicenter, single-arm phase II clinical trial (ACT III) was performed to confirm these results. Rindopepimut and standard adjuvant temozolomide chemotherapy were administered to 65 patients with newly diagnosed EGFRvIII-expressing (EGFRvIII+) glioblastoma after gross total resection and chemoradiation. Progression-free survival at 5.5 months (∼8.5 mo from diagnosis) was 66%. Relative to study entry, median overall survival was 21.8 months, and 36-month overall survival was 26%. Extended rindopepimut vaccination (up to 3.5+ years) was well tolerated. Grades 1-2 injection site reactions were frequent. Anti-EGFRvIII antibody titers increased ≥4-fold in 85% of patients, and increased with duration of treatment. EGFRvIII was eliminated in 4/6 (67%) tumor samples obtained after >3 months of therapy. This study confirms, in a multicenter setting, the preliminary results seen in previous phase II trials of rindopepimut. A pivotal, double-blind, randomized, phase III trial ("ACT IV") is under way. © The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
    Neuro-oncology. 01/2015;
  • Peter E Fecci, Amy B Heimberger, John H Sampson
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    ABSTRACT: Immunotherapy for cancer continues to gain both momentum and legitimacy as a rational mode of therapy and a vital treatment component in the emerging era of personalized medicine. Gliomas, and their most malignant form, glioblastoma, remain as a particularly devastating solid tumor for which standard treatment options proffer only modest efficacy and target specificity. Immunotherapy would seem a well-suited choice to address such deficiencies given both the modest inherent immunogenicity of gliomas and the strong desire for treatment specificity within the confines of the toxicity-averse normal brain. This review highlights the caveats and challenges to immunotherapy for primary brain tumors, as well as reviewing modalities that are currently used or are undergoing active investigation. Tumor immunosuppressive countermeasures, peculiarities of central nervous system immune access, and opportunities for rational treatment design are discussed. See all articles in this CCR Focus section, "Discoveries, Challenges, and Progress in Primary Brain Tumors." Clin Cancer Res; 20(22); 5620-9. ©2014 AACR.
    Clinical Cancer Research 11/2014; 20(22):5620-9. · 8.19 Impact Factor
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    ABSTRACT: Subependymomas are usually treated with surgical resection; however, no standard, defined alternative medical therapy is recommended for patients who are not surgical candidates, owing to a paucity of molecular, immunological, and genetic characterization. To address this, an ex vivo functional analysis of the immune microenvironment in subependymoma was conducted, a subependymoma cytokine/chemokine microarray was constructed for the evaluation of operational immune and molecular pathways, and a subependymoma cell line was derived and used to test a variety of cytotoxic agents that target operational pathways identified in subependymoma. We found that immune effectors are detectable within the microenvironment of subependymoma; however, marked immune suppression is not observed. The subependymoma tissue microarrays demonstrated tumor expression of p53, MDM2, HIF-1α, topoisomerase II-β, p-STAT3, and nucleolin, but not EGFRvIII, EphA2, IL-13RA2, CMV, CTLA-4, FoxP3, PD-1, PD-L1, EGFR, PDGF-α, PDGF-β, PDGFR-α, PDGFR-β, PTEN, IGFBP2, PI3K, MDM4, IDH1, mTOR, or Jak2. A topoisomerase inhibitor (WP744, IC50=0.83μM) and a p-STAT3/HIF-1α inhibitor (WP1066, IC50=3.15μM) demonstrated a growth inhibition of the subependymoma cell proliferation. Cumulatively, these data suggest that those agents that interfere with oncogenes operational in subependymoma may have clinical impact. Copyright © 2014 Elsevier B.V. All rights reserved.
    Journal of Neuroimmunology 10/2014; 277(1-2):168-175. · 2.79 Impact Factor
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    ABSTRACT: Signal transducer and activator of transcription 5b (STAT5b) is likely the relevant STAT5 isoform with respect to the process of malignant progression in gliomas. STAT5b is a latent cytoplasmic protein involved in cell signaling through the modulation of growth factors, apoptosis, and angiogenesis. Previous in vitro studies have shown increased STAT5b expression in glioblastomas relative to low-grade tumors and normal brain. We recently demonstrated that phosphorylated STAT5b associates with delta epidermal growth factor receptor in the nucleus and subsequently binds the promoters of downstream effector molecules, including aurora kinase A. Analysis of TCGA dataset reveals that STAT5b is predominantly expressed in proneural (PN) gliomas relative to mesenchymal and neural gliomas. Here, we modeled ectopic expression of STAT5b in vivo using a platelet-derived growth factor subunit B (PDGFB)-dependent mouse model of PN glioma to determine its effect on tumor formation and progression. We showed that co-expression of STAT5b and PDGFB in mice yielded a significantly higher rate of high-grade gliomas than PDGFB expression alone. We also observed shorter survival in the combined expression set. High-grade tumors from the STAT5b+PDGFB expression set were found to have a lower rate of apoptosis than those from PDGFB alone. Furthermore, we showed that increased expression of STAT5b+PDGFB led to increased expression of downstream STAT5b targets, including Bcl-xL, cyclin D1, and aurora kinase A in high-grade tumors when compared to tumors derived from PDGFB alone. Our findings show that STAT5b promotes the malignant transformation of gliomas, particularly the PN subtype, and is a potential therapeutic target. © 2014 Wiley Periodicals, Inc.
    International Journal of Cancer 10/2014; · 6.20 Impact Factor
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    ABSTRACT: Immunotherapeutic approaches to cancer have shown remarkable promise. A critical barrier to successfully executing such immune-mediated interventions is the selection of safe yet immunogenic targets. As patient deaths have occurred when tumor-associated antigens shared by normal tissue have been targeted by strong cellular immunotherapeutic platforms, route of delivery, target selection and the immune-mediated approach undertaken must work together to maximize efficacy with safety. Selected tumor-specific targets can spare potential toxicity to normal tissue; however, they are far less common than tumor-associated antigens and may not be present on all patients. In the context of immunotherapy for high-grade glioma, 2 of the most prominently studied antigens are the tumor-associated epidermal growth factor receptor and its tumor-specific genetic deletion variant III. In this review, we will summarize the immune-mediated strategies employed against these targets as well as the caveats particular to these approaches.
    Neuro-Oncology 10/2014; 16(suppl 8):viii20-viii25. · 5.29 Impact Factor
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    ABSTRACT: Fibrinogen-like protein 2 (Fgl2), a member of the fibrinogen family, can be expressed as a membrane-associated protein with coagulation activity or in a secreted form possessing unique immune suppressive functions. The biological importance of Fgl2 is evident within viral-induced fibrin depositing inflammatory diseases and malignancies and provides a compelling rationale for Fgl2 expression to not only be considered as a disease biomarker but also as a therapeutic target. This article will provide a comprehensive review of the currently known biological properties of Fgl2 and clarifies future scientific directives.
    International Reviews Of Immunology 09/2014; · 5.28 Impact Factor
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    ABSTRACT: The immune therapeutic potential of microRNAs (miRNAs) in the context of tumor-mediated immune suppression has not been previously described for monocyte-derived glioma-associated macrophages, which are the largest infiltrating immune cell population in glioblastomas and facilitate gliomagenesis.
    JNCI Journal of the National Cancer Institute 08/2014; 106(8). · 15.16 Impact Factor
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    ABSTRACT: Despite the recent successes of using immune modulatory antibodies in cancer patients, autoimmune pathologies resulting from the activation of self self-reactive T cells preclude the dose escalations necessary to fully exploit their therapeutic potential. To reduce the observed and expected toxicities associated with immune modulation, here we describe a clinically feasible and broadly applicable approach to limit immune costimulation to the disseminated tumor lesions of the patient whereby an agonistic 4-1BB oligonucleotide aptamer is targeted to the tumor stroma by conjugation to an aptamer that binds to a broadly expressed stromal product, vascular endothelial growth factor (VEGF). The approach was predicated on the premise that by targeting the costimulatory ligands to products secreted into the tumor stroma the T cells will be costimulated prior to their engagement of the MHC/peptide complex on the tumor cell, thereby obviating the need to target the costimulatory ligands to non-internalizing cell cell-surface products expressed on the tumor cells. Underscoring the potency of stroma stroma-targeted costimulation and the broad spectrum of tumors secreting VEGF, in preclinical murine tumor models systemic administration of the VEGF VEGF-targeted 4-1BB aptamer conjugates engendered potent antitumor immunity against multiple unrelated tumors in subcutaneous, post post-surgical lung metastasis, methylcholantrene-induced fibrosarcoma, and oncogene-induced autochthonous glioma models, and exhibited a superior therapeutic index compared to non-targeted administration of an agonistic 4-1BB antibody or 4-1BB aptamer.
    Cancer immunology research. 06/2014;
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    ABSTRACT: Despite extensive study, few therapeutic targets have been identified for glioblastoma (GBM). Here we show that patient-derived glioma sphere cultures (GSCs) that resemble either the proneural (PN) or mesenchymal (MES) transcriptomal subtypes differ significantly in their biological characteristics. Moreover, we found that a subset of the PN GSCs undergoes differentiation to a MES state in a TNF-a/ NF-kB-dependent manner with an associated enrichment of CD44 subpopulations and radioresistant phenotypes. We present data to suggest that the tumor microenvironment cell types such as macro-phages/microglia may play an integral role in this process. We further show that the MES signature, CD44 expression, and NF-kB activation correlate with poor radiation response and shorter survival in patients with GBM. Significance In this study, we characterize plasticity between the proneural (PN) and mesenchymal (MES) transcriptome signatures observed in glioblastoma (GBM). Specifically, we show that PN glioma sphere cultures (GSCs) can be induced to a MES state with an associated enrichment of CD44 expressing cells and a gain of radioresistance, in an NF-kB-dependent fashion. Newly diagnosed GBM samples show a direct correlation among radiation response, higher MES metagene, CD44 expres-sion, and NF-kB activation, and we propose macrophages/microglia as a potential microenvironmental component that can regulate this transition. Our results reveal a mechanistic link between transcriptome plasticity, radiation resistance, and NF-kB signaling. Inhibition of NF-kB activation can directly affect radioresistance and presents an attractive therapeutic target for GBM.
    Cancer Cell 09/2013; 24:331-346. · 23.89 Impact Factor
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    ABSTRACT: Despite extensive study, few therapeutic targets have been identified for glioblastoma (GBM). Here we show that patient-derived glioma sphere cultures (GSCs) that resemble either the proneural (PN) or mesenchymal (MES) transcriptomal subtypes differ significantly in their biological characteristics. Moreover, we found that a subset of the PN GSCs undergoes differentiation to a MES state in a TNF-α/NF-κB-dependent manner with an associated enrichment of CD44 subpopulations and radioresistant phenotypes. We present data to suggest that the tumor microenvironment cell types such as macrophages/microglia may play an integral role in this process. We further show that the MES signature, CD44 expression, and NF-κB activation correlate with poor radiation response and shorter survival in patients with GBM.
    Cancer cell 08/2013; · 25.29 Impact Factor
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    ABSTRACT: The molecular heterogeneity of glioblastoma has been well recognized and has resulted in the generation of molecularly defined subtypes. These subtypes (classical, neural, mesenchymal, and proneural) are associated with particular signaling pathways and differential patient survival. Less understood is the correlation between these glioblastoma subtypes with immune system effector responses, immune suppression and tumor-associated and tumor-specific antigens. The role of the immune system is becoming increasingly relevant to treatment as new agents are being developed to target mediators of tumor-induced immune suppression which is well documented in glioblastoma. To ascertain the association of antigen expression, immune suppression, and effector response genes within glioblastoma subtypes, we analyzed the Cancer Genome Atlas (TCGA) glioblastoma database. We found an enrichment of genes within the mesenchymal subtype that are reflective of anti-tumor proinflammatory responses, including both adaptive and innate immunity and immune suppression. These results indicate that distinct glioma antigens and immune genes demonstrate differential expression between glioblastoma subtypes and this may influence responses to immune therapeutic strategies in patients depending on the subtype of glioblastoma they harbor.
    Cancer immunology research. 08/2013; 1(112).
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    Amy B Heimberger, Mark Gilbert, Ganesh Rao, Jun Wei
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    ABSTRACT: A large unmet need exists for cost-effective, widely available antineoplastic immunotherapeutic agents with a robust translational potential. MicroRNAs (miRNAs) that regulate tumor-mediated immunosuppression or immune checkpoints can induce robust therapeutic immune responses, indicating that miRNAs may ultimately become part of the portfolio of anticancer immunotherapeutics.
    OncoImmunology 08/2013; 2(8):e25124. · 6.28 Impact Factor
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    ABSTRACT: MicroRNAs (miRs) have been shown to modulate critical gene transcripts involved in tumorigenesis, but their role in tumor-mediated immune suppression is largely unknown. On the basis of miRNA gene expression in gliomas using tissue microarrays, in situ hybridization, and molecular modeling, miR-124 was identified as a lead candidate for modulating signal transducer and activator of transcription 3 (STAT3) signaling, a key pathway mediating immune suppression in the tumor microenvironment. miR-124 is absent in all grades and pathological types of gliomas. Upon up regulating miR-124 in glioma cancer stem cells (gCSCs), the STAT3 pathway was inhibited, and miR-124 reversed gCSC-mediated immune suppression of T-cell proliferation and induction of Foxp3+ regulatory T-cells (Tregs). Treatment of T-cells from immunosuppressed glioblastoma patients with miR-124 induced marked effector response including up regulation of IL-2, IFN-γ, and tumor necrosis factor (TNF)-α. Both systemic administration of miR-124 or adoptive miR-124-transfected T-cell transfers exerted potent anti-glioma therapeutic effects in clonotypic and genetically engineered murine models of glioblastoma and enhanced effector responses in the local tumor microenvironment. These therapeutic effects were ablated in both CD4+ and CD8+ depleted mice and nude mouse systems, indicating that the therapeutic effect of miR-124 depends on the presence of a T-cell-mediated antitumor immune response. Our findings highlight the potential application of miR-124 as a novel immunotherapeutic agent for neoplasms and serve as a model for identifying miRNAs that can be exploited as immune therapeutics.
    Cancer Research 05/2013; · 9.28 Impact Factor
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    ABSTRACT: B lymphocyte stimulator (BLyS) is a cytokine involved in differentiation and survival of follicular B cells along with humoral response potentiation. Lymphopenia is known to precipitate dramatic elevation in serum BLyS; however, the use of this effect to enhance humoral responses following vaccination has not been evaluated. We evaluated BLyS serum levels and antigen-specific antibody titers in 8 patients undergoing therapeutic temozolomide (TMZ)-induced lymphopenia, with concomitant vaccine against a tumor-specific mutation in the epidermal growth factor receptor (EGFRvIII). Our studies demonstrate that TMZ-induced lymphopenia corresponded with spikes in serum BLyS that directly preceded the induction of anti-EGFRvIII antigen-specific antibody titers, in some cases as high as 1:2,000,000. Our data are the first clinical observation of BLyS serum elevation and greatly enhanced humoral immune responses as a consequence of chemotherapy-induced lymphopenia. These observations should be considered for the development of future vaccination strategies in the setting of malignancy.
    Cancer Immunology and Immunotherapy 04/2013; · 3.64 Impact Factor
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    ABSTRACT: Object Seizures are a potentially devastating complication of resection of brain tumors. Consequently, many neurosurgeons administer prophylactic antiepileptic drugs (AEDs) in the perioperative period. However, it is currently unclear whether perioperative AEDs should be routinely administered to patients with brain tumors who have never had a seizure. Therefore, the authors conducted a prospective, randomized trial examining the use of phenytoin for postoperative seizure prophylaxis in patients undergoing resection for supratentorial brain metastases or gliomas. Methods Patients with brain tumors (metastases or gliomas) who did not have seizures and who were undergoing craniotomy for tumor resection were randomized to receive either phenytoin for 7 days after tumor resection (prophylaxis group) or no seizure prophylaxis (observation group). Phenytoin levels were monitored daily. Primary outcomes were seizures and adverse events. Using an estimated seizure incidence of 30% in the observation arm and 10% in the prophylaxis arm, a Type I error of 0.05 and a Type II error of 0.20, a target accrual of 142 patients (71 per arm) was planned. Results The trial was closed before completion of accrual because Bayesian predictive probability analyses performed by an independent data monitoring committee indicated a probability of 0.003 that at the end of the study prophylaxis would prove superior to observation and a probability of 0.997 that there would be insufficient evidence at the end of the trial to choose either arm as superior. At the time of trial closure, 123 patients (77 metastases and 46 gliomas) were randomized, with 62 receiving 7-day phenytoin (prophylaxis group) and 61 receiving no prophylaxis (observation group). The incidence of all seizures was 18% in the observation group and 24% in the prophylaxis group (p = 0.51). Importantly, the incidence of early seizures (< 30 days after surgery) was 8% in the observation group compared with 10% in the prophylaxis group (p = 1.0). Likewise, the incidence of clinically significant early seizures was 3% in the observation group and 2% in the prophylaxis group (p = 0.62). The prophylaxis group experienced significantly more adverse events (18% vs 0%, p < 0.01). Therapeutic phenytoin levels were maintained in 80% of patients. Conclusions The incidence of seizures after surgery for brain tumors is low (8% [95% CI 3%-18%]) even without prophylactic AEDs, and the incidence of clinically significant seizures is even lower (3%). In contrast, routine phenytoin administration is associated with significant drug-related morbidity. Although the lower-than-anticipated incidence of seizures in the control group significantly limited the power of the study, the low baseline rate of perioperative seizures in patients with brain tumors raises concerns about the routine use of prophylactic phenytoin in this patient population.
    Journal of Neurosurgery 02/2013; · 3.15 Impact Factor
  • Journal for ImmunoTherapy of Cancer. 01/2013; 1(Suppl 1):P177.
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    Jun Wei, Konrad Gabrusiewicz, Amy Heimberger
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    ABSTRACT: Malignant gliomas contain stroma and a variety of immune cells including abundant activated microglia/macrophages. Mounting evidence indicates that the glioma microenvironment converts the glioma-associated microglia/macrophages (GAMs) into glioma-supportive, immunosuppressive cells; however, GAMs can retain intrinsic anti-tumor properties. Here, we review and discuss this duality and the potential therapeutic strategies that may inhibit their glioma-supportive and propagating functions.
    Clinical and Developmental Immunology 01/2013; 2013:285246. · 2.93 Impact Factor
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    ABSTRACT: Determining the mechanism of treatment failure of VEGF signaling inhibitors for malignant glioma patients would provide insight into approaches to overcome therapeutic resistance. In this study, we demonstrate that human glioblastoma tumors failing bevacizumab have an increase in the mean percentage of p-STAT3-expressing cells compared to samples taken from patients failing non-antiangiogenic therapy containing regimens. Likewise, in murine xenograft models of glioblastoma, the mean percentage of p-STAT3-expressing cells in the gliomas resistant to antiangiogenic therapy was markedly elevated relative to controls. Administration of the JAK/STAT3 inhibitor AZD1480 alone and in combination with cediranib reduced tumor hypoxia and the infiltration of VEGF inhibitor-induced p-STAT3 macrophages. Thus, the combination of AZD1480 with cediranib markedly reduced tumor volume, and microvascular density, indicating that up regulation of the STAT3 pathway can mediate resistance to antiangiogenic therapy and combinational approaches may delay or overcome resistance.
    Oncotarget 09/2012; 3(9):1036-48. · 6.63 Impact Factor
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    ABSTRACT: Signal transducer and activator of transcription (STAT) 3 has been described as a "master regulator" of signaling pathways involved in the transition from low-grade glioma (LGG) to high-grade glioma (HGG). Although STAT3 is overexpressed in HGGs, it remains unclear whether its overexpression is sufficient to induce or promote the malignant progression of glioma. To characterize the effect of STAT3 expression on tumor progression in vivo, we expressed the STAT3 gene in glioneuronal progenitor cells in mice. STAT3 was expressed alone or concurrently with platelet-derived growth factor B (PDGFB), a well-described initiator of LGG. STAT3 alone was insufficient to induce tumor formation; however, coexpression of STAT3 with PDGFB in mice resulted in a significantly higher incidence of HGGs than PDGFB alone. The median symptomatic tumor latency in mice coexpressing STAT3 and PDGFB was significantly shorter, and mice that developed symptomatic tumors demonstrated significantly higher expression of phosphorylated STAT3 intratumorally. In HGGs, expression of STAT3 was associated with suppression of apoptosis and an increase in tumor cell proliferation. HGGs induced by STAT3 and PDGFB also displayed frequent foci of necrosis and microvascular proliferation. The expression of CD31 (a marker of endothelial proliferation) was significantly higher in tumors induced by coexpression of STAT3 and PDGFB. When mice injected with PDGFB and STAT3 were treated with a STAT3 inhibitor, median survival increased and the incidence of HGG and CD31 expression decreased significantly. These results demonstrate that STAT3 promotes the malignant progression of glioma. Inhibiting STAT3 expression mitigates tumor progression and improves survival, validating it as a therapeutic target.
    Neuro-Oncology 06/2012; 14(9):1136-45. · 5.29 Impact Factor

Publication Stats

3k Citations
472.43 Total Impact Points

Institutions

  • 2002–2014
    • University of Texas MD Anderson Cancer Center
      • • Department of NeuroSurgery
      • • Department of Cancer Biology
      Houston, Texas, United States
  • 2000–2013
    • Duke University Medical Center
      • • Division of Neurosurgery
      • • Department of Surgery
      Durham, NC, United States
  • 2008–2010
    • University of Houston
      Houston, Texas, United States