Theresa L Whiteside

University of Pittsburgh, Pittsburgh, Pennsylvania, United States

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Publications (668)3057.63 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Purpose: We conducted a double-blind, placebo-controlled trial to evaluate the effect of granulocyte-macrophage colony-stimulating factor (GM-CSF) and peptide vaccination (PV) on relapse-free survival (RFS) and overall survival (OS) in patients with resected high-risk melanoma. Patients and methods: Patients with completely resected stage IV or high-risk stage III melanoma were grouped by human leukocyte antigen (HLA) -A2 status. HLA-A2-positive patients were randomly assigned to receive GM-CSF, PV, both, or placebo; HLA-A2-negative patients, GM-CSF or placebo. Treatment lasted for 1 year or until recurrence. Efficacy analyses were conducted in the intent-to-treat population. Results: A total of 815 patients were enrolled. There were no significant improvements in OS (stratified log-rank P = .528; hazard ratio, 0.94; 95% repeated CI, 0.77 to 1.15) or RFS (P = .131; hazard ratio, 0.88; 95% CI, 0.74 to 1.04) in the patients assigned to GM-CSF (n = 408) versus those assigned to placebo (n = 407). The median OS times with GM-CSF versus placebo treatments were 69.6 months (95% CI, 53.4 to 83.5 months) versus 59.3 months (95% CI, 44.4 to 77.3 months); the 5-year OS probability rates were 52.3% (95% CI, 47.3% to 57.1%) versus 49.4% (95% CI, 44.3% to 54.3%), respectively. The median RFS times with GM-CSF versus placebo were 11.4 months (95% CI, 9.4 to 14.8 months) versus 8.8 months (95% CI, 7.5 to 11.2 months); the 5-year RFS probability rates were 31.2% (95% CI, 26.7% to 35.9%) versus 27.0% (95% CI, 22.7% to 31.5%), respectively. Exploratory analyses showed a trend toward improved OS in GM-CSF-treated patients with resected visceral metastases. When survival in HLA-A2-positive patients who received PV versus placebo was compared, RFS and OS were not significantly different. Treatment-related grade 3 or greater adverse events were similar between GM-CSF and placebo groups. Conclusion: Neither adjuvant GM-CSF nor PV significantly improved RFS or OS in patients with high-risk resected melanoma. Exploratory analyses suggest that GM-CSF may be beneficial in patients with resected visceral metastases; this observation requires prospective validation.
    Journal of Clinical Oncology 09/2015; DOI:10.1200/JCO.2015.62.0500 · 18.43 Impact Factor
  • Theresa L Whiteside
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    ABSTRACT: Tumor-derived exosomes (TEX) are emerging as a new type of cancer biomarker. TEX are membrane-bound, virus-size vesicles of endocytic origin present in all body fluids of cancer patients. Based on the expanding albeit incomplete knowledge of their biogenesis, secretion by tumor cells and cancer cell-specific molecular and genetic contents, TEX are viewed as promising, clinically-relevant surrogates of cancer progression and response to therapy. Preliminary proteomic, genetic and functional profiling of tumor cell-derived or cancer plasma-derived exosomes confirms their unique characteristics. Alterations in protein or nucleic acid profiles of exosomes in plasma of cancer patients responding to therapies appear to correlate with clinical endpoints. However, methods for TEX isolation and separation from the bulk of human plasma-derived exosomes are not yet established and their role as biomarkers remains to be confirmed. Further development and validation of TEX as noninvasive, liquid equivalents of tumor biopsies are necessary to move this effort forward.
    Expert Review of Molecular Diagnostics 08/2015; 15(10):1-18. DOI:10.1586/14737159.2015.1071666 · 3.52 Impact Factor
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    ABSTRACT: Regulatory T cell (Treg)-mediated immunosuppression is considered a major obstacle for successful cancer immunotherapy. The association between clinical outcome and Tregs is being studied extensively in clinical trials, but unfortunately, no consensus has been reached about (a) the markers and (b) the gating strategy required to define human Tregs in this context, making it difficult to draw final conclusions. Therefore, we have organized an international workshop on the detection and functional testing of Tregs with leading experts in the field, and 40 participants discussing different analyses and the importance of different markers and context in which Tregs were analyzed. This resulted in a rationally composed ranking list of "Treg markers". Subsequently, the proposed Treg markers were tested to get insight into the overlap/differences between the most frequently used Treg definitions and their utility for Treg detection in various human tissues. Here, we conclude that the CD3, CD4, CD25, CD127, and FoxP3 markers are the minimally required markers to define human Treg cells. Staining for Ki67 and CD45RA showed to provide additional information on the activation status of Tregs. The use of markers was validated in a series of PBMC from healthy donors and cancer patients, as well as in tumor-draining lymph nodes and freshly isolated tumors. In conclusion, we propose an essential marker set comprising antibodies to CD3, CD4, CD25, CD127, Foxp3, Ki67, and CD45RA and a corresponding robust gating strategy for the context-dependent analysis of Tregs by flow cytometry.
    Cancer Immunology and Immunotherapy 06/2015; 64(10). DOI:10.1007/s00262-015-1729-x · 3.94 Impact Factor
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    Michael Boyiadzis · Theresa L Whiteside · Steven Z Pavletic
    Aging 06/2015; 7(6). · 6.43 Impact Factor
  • Alison Sehgal · Theresa L Whiteside · Michael Boyiadzis
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    ABSTRACT: Introduction: Immune checkpoints are regulatory pathways induced in activated T lymphocytes that regulate antigen responsiveness. These immune checkpoints are hijacked by tumors to promote dysfunction of anti-tumor effector cells and consequently of tumor escape from the host immune system. Areas covered: Programmed death-1/programmed death ligand (PD-1/PDL-1), a checkpoint pathway, has been extensively investigated in leukemia mouse models. Expression of PD-1 on the surface of activated immune cells and of its ligands, PD-L1 and PD-L2, on leukemic blasts has been documented. Clinical trials with PD-1 inhibitors in patients with hematological malignancies are ongoing with promising clinical responses. Expert opinion: Therapy of hematological cancers with antibodies blocking inhibitory receptors is expected to be highly clinically effective. Checkpoint inhibitory receptors and their ligands are co-expressed on hematopoietic cells found in the leukemic milieu. Several distinct immunological mechanisms are likely to be engaged by antibody-based checkpoint blockade. Co-expression of multiple inhibitory receptors on hematopoietic cells offers an opportunity for combining blocking antibodies to achieve more effective therapy. Up-regulation of receptor/ligand expression in the leukemic milieu may provide a blood marker predictive of response. Finally, chemotherapy-induced up-regulation of PD-1 on T cells after conventional leukemia therapy creates a solid rationale for application of checkpoint blockade as a follow-up therapy.
    Expert opinion on biological therapy 06/2015; 15(8). DOI:10.1517/14712598.2015.1051028 · 3.74 Impact Factor
  • L. Muller · P. Simms · M. Nishimura · S. Watkins · T. Whiteside
    Oral Oncology 05/2015; 51(5):e33. DOI:10.1016/j.oraloncology.2015.02.020 · 3.61 Impact Factor
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    ABSTRACT: The EGFR-targeted antibody cetuximab is effective against head and neck cancer (HNC), but in only 15-20% of patients, and the variability and extent of cetuximab-mediated cellular immunity is not fully understood. We hypothesized that regulatory T cells (Treg) may exert a functional and clinical impact on antitumor immunity in cetuximab-treated individuals. The frequency, immunosuppressive phenotype and activation status of Treg and NK cells were analyzed in the circulation and tumor microenvironment of cetuximab-treated HNC patients enrolled in a novel neoadjuvant, single-agent cetuximab clinical trial. Notably, cetuximab treatment increased the frequency of CD4+FOXP3+ intratumoral Treg expressing CTLA-4, CD39 and TGF-β. These Treg suppressed cetuximab-mediated ADCC and their presence correlated with poor clinical outcome two prospective trial cohorts. Cetuximab expanded CTLA-4+FOXP3+ Treg in vitro, in part by inducing DC maturation, in combination with TGF-β and TCR triggering. Importantly, cetuximab-activated NK cells selectively eliminated intratumoral Treg but preserved effector T cells. In ex vivo assays, ipilimumab targeted CTLA-4+ Treg and restored cytolytic functions of NK cells mediating ADCC. Taken together, our results argue that differences in Treg-mediated suppression contribute to the clinical response to cetuximab treatment, suggesting its improvement by adding ipilimumab or other strategies of Treg ablation to promote anti-tumor immunity. Copyright © 2015, American Association for Cancer Research.
    Cancer Research 04/2015; 75(11). DOI:10.1158/0008-5472.CAN-14-2788 · 9.33 Impact Factor
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    ABSTRACT: Whereas preclinical investigations and clinical studies have established that CD8(+) T cells can profoundly affect cancer progression, the underlying mechanisms are still elusive. Challenging the prevalent view that the beneficial effect of CD8(+) T cells in cancer is solely attributable to their cytotoxic activity, several reports have indicated that the ability of CD8(+) T cells to promote tumor regression is dependent on their cytokine secretion profile and their ability to self-renew. Evidence has also shown that the tumor microenvironment can disarm CD8(+) T cell immunity, leading to the emergence of dysfunctional CD8(+) T cells. The existence of different types of CD8(+) T cells in cancer calls for a more precise definition of the CD8(+) T cell immune phenotypes in cancer and the abandonment of the generic terms "pro-tumor" and "antitumor." Based on recent studies investigating the functions of CD8(+) T cells in cancer, we here propose some guidelines to precisely define the functional states of CD8(+) T cells in cancer.
    OncoImmunology 04/2015; 4(4):e998538. DOI:10.1080/2162402X.2014.998538 · 6.27 Impact Factor
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    ABSTRACT: Background: An autologous vaccine of apoptotic tumor cells (ATC) & dendritic cells (DC) was administered to stage III/IV HNSCC patients to study safety and feasibility. Methods: Autologous DC were generated from monocytes, loaded with ATC and delivered intranodally. Delayed-type hypersensitivity (DTH) and immunological endpoints were measured pre/post vaccination. Clinical follow-up was required. Results: Tumors obtained from 30 patients yielded 2x10(6) - 2x10(8) tumor cells. Only 19/30 (63%) were sterile. 10/30 patients (33%) had ≥1x10(7) sterile tumor cells required for vaccine production. 8/10 had positive recall DTH. 5/10 were leukapheresed to generate DC. 4/5 were vaccinated. ATC-reactive T cells were detected in 3/4 patients. All 4 survived > 5 years. The trial failed to enroll the projected 12 patients and was terminated. Conclusions: This vaccine was safe and immunogenic but feasible only in HNSCC patients with positive pre-vaccine DTH and ≥1x10(7) sterile tumor cells. All vaccinated patients were long-term disease-free survivors. [Words, 150] This article is protected by copyright. All rights reserved. © 2015 Wiley Periodicals, Inc.
    Head & Neck 03/2015; DOI:10.1002/hed.24025 · 2.64 Impact Factor
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    ABSTRACT: Exosomes in plasma of glioma patients hold promise as biomarkers of prognosis. We aimed to determine whether changes in total exosomal protein and mRNA expression levels could serve as surrogate markers of immunological and clinical responses in glioma patients receiving antitumor vaccines. Exosomes were isolated from pre/post-vaccine plasma specimens in 20/22 patients enrolled in a phase I/II trial with the antitumor vaccine. Exosomal protein content was analyzed and mRNA expression levels for 24 genes were simultaneously assessed by qRT-PCR. Pre- to post-vaccination changes in exosomal protein and ΔCt values were correlated with immunological and clinical responses and survival using Spearman rank statistics and hazard ratios (HR). Exosomal protein levels positively correlated (p < 0.0043) with the WHO tumor grade at diagnosis. Protein levels were lower in post- vs. pre-vaccination exosome fractions. Post-therapy increases in tumor size were associated with elevations in exosome proteins in glioblastoma but not always in anaplastic astrocytoma (AA). Only exosomal ΔCt values for IL-8, TIMP-1, TGF-β and ZAP70 were significant (p < 0.04 to p < 0.001). The ΔCt for IL-8 and TGF-β mRNA positively correlated with post-vaccine immunologic responses to glioma antigens, while ΔCt for TIMP-1 mRNA was negatively correlated to ΔCt for IL-8 and TGF-β. Only ΔCt for IL-8 weakly correlated with OS and time to progression (TTP). In post-vaccine exosomes of the longest surviving patient with AA, mRNA for PD-1 was persistently elevated. Protein and mRNA expression levels for immune-related genes in plasma exosomes were useful in evaluating glioma patients' response to vaccination therapy.
    OncoImmunology 03/2015; 4(6):e1008347. DOI:10.1080/2162402X.2015.1008347 · 6.27 Impact Factor
  • Moon Fenton · Theresa L Whiteside · Soldano Ferrone · Michael Boyiadzis
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    ABSTRACT: Chondroitin sulfate proteoglycan-4 (CSPG4), a membrane-bound proteoglycan known to be expressed on the surface of malignant cells, has a restricted distribution in normal tissues. CSPG4 is a potential candidate tumor marker. We investigate CSPG4 expression on blasts in newly diagnosed acute myeloid leukemia (AML) patients and its relation with cytogenetic abnormalities and molecular markers known to have prognostic significance in this disease. Using hybridoma technology, we generated a specific monoclonal antibody (mAb), mAb 225.28, reactive with CSPG4. Blast samples obtained from the peripheral blood of newly diagnosed AML patients were analyzed for CSPG4 expression using the CSPG4-specific mAb and multiparameter flow cytometry. The results were correlated with cytogenetic and molecular characteristics of AML. CSPG4 was found to be expressed on a variable fraction of leukemic blasts in all AML patients with different leukemia morphology, including monoblastic cases. Reactivity of CSPG4-specific mAb with leukemic blasts was not limited to those with the rearranged MLL gene. CSPG4 was also expressed on AML blasts with a complex karyotype, FLT3 mutation, or NPM1 mutation. The results indicate that CSPG4 is expressed and detectable by flow cytometry using the mAb 225.28 on a proportion of blasts of all subtypes of AML irrespective of cytogenetic and molecular abnormalities. mAb 225.28 could be useful in detecting AML blasts by flow cytometry.
    Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics 02/2015; 22(2):117-21. DOI:10.3727/096504014X14174484758503 · 1.06 Impact Factor
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    Michael Boyiadzis · Theresa L. Whiteside
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    ABSTRACT: Exosomes are small (30-150mm) vesicles secreted by all cell types and present in all body fluids. They are emerging as vehicles for delivery of membrane-tethered signaling molecules and membrane enclosed genes to target cells. Exosome-mediated information transfer allows for crosstalk of cells within the hematopoietic system and for interactions between hematopoietic cells and local or distant tissue cells. Exosomes carry physiological signals essential for health and participate in pathological processes, including malignant transformation. In hematologic malignancies, exosomes reprogram the bone marrow microenvironment, creating a niche for abnormal cells and favoring their expansion. The molecular and genetic mechanisms exosomes utilize to shuttle information between cells are currently being examined as are the potential roles exosomes play as biomarkers of disease or future therapeutic targets. Copyright © 2015. Published by Elsevier Ltd.
    Blood Reviews 01/2015; 9(5). DOI:10.1016/j.blre.2015.01.004 · 5.57 Impact Factor
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    ABSTRACT: During the past decades, anticancer immunotherapy has evolved from a promising therapeutic option to a robust clinical reality. Many immunotherapeutic regimens are now approved by the US Food and Drug Administration and the European Medicines Agency for use in cancer patients, and many others are being investigated as standalone therapeutic interventions or combined with conventional treatments in clinical studies. Immunotherapies may be subdivided into "passive" and "active" based on their ability to engage the host immune system against cancer. Since the anticancer activity of most passive immunotherapeutics (including tumor-targeting monoclonal antibodies) also relies on the host immune system, this classification does not properly reflect the complexity of the drug-host-tumor interaction. Alternatively, anticancer immunotherapeutics can be classified according to their antigen specificity. While some immunotherapies specifically target one (or a few) defined tumor-associated antigen(s), others operate in a relatively non-specific manner and boost natural or therapy-elicited anticancer immune responses of unknown and often broad specificity. Here, we propose a critical, integrated classification of anticancer immunotherapies and discuss the clinical relevance of these approaches.
    Oncotarget 12/2014; 5(24). DOI:10.18632/oncotarget.2998 · 6.36 Impact Factor
  • Theresa L Whiteside
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    ABSTRACT: The role of regulatory T cells, (Treg) in human cancer and HIV-1 infections has been under intense scrutiny. While the lack of a marker specific for human Treg has made it challenging to phenotype these cells, combinations of several markers and functional attributes of Treg have made it possible to assess their contributions to immune homeostasis in health and disease. Treg diversity and their plasticity create a challenge in deciding whether they are beneficial to the host by down-regulating excessive immune activation or are responsible for adverse effects such as suppression of anti-tumor immune responses resulting in promotion of tumor growth. Treg are emerging as active participants in several biochemical pathways involved in immune regulation. This review attempts to integrate current information about human Treg in respect to their activities in cancer and HIV-1. The goal is to evaluate the potential of Treg as targets for future immune or pharmacologic therapies for cancer or HIV-1 infections.
    Cancer Microenvironment 11/2014; DOI:10.1007/s12307-014-0159-1
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    ABSTRACT: Cholesteatoma represents progressive expansion of the keratinizing squamous epithelium in the middle ear with subsequent chronic inflammation in subepithelial connective tissues. The hypothesis was tested that receptor for advanced glycation endproduct (RAGE) and its ligand, high-mobility box 1 (HMGB1), are overexpressed in cholesteatoma, and the RAGE/HMGB1 axis might contribute to its pathogenesis. Cholesteatoma samples (n = 36) and 27 normal skin specimens were studied by immunohistochemistry (IHC) for HMGB1 and RAGE expression. Effects of HMGB1 signaling on proliferation, migration, cytokine production, and apoptosis of human immortalized keratinocytes (HaCaTs) and normal keratinocytes were studied by quantitative reverse transcription (qRT)-PCR, IHC, Western blots, and flow cytometry after cell co-incubation with HMGB1. While all studied tissues expressed HMGB1, its expression was higher in cholesteatoma than in normal skin (p < 0.0001). All cases of cholesteatoma also showed elevated RAGE expression levels, and only 7/27 (26 %) of normal skin specimens were weakly positive for RAGE. Proliferation and migration of HaCaT cells incubated with HMGB1 were up-regulated (p < 0.05). HMGB1 also prevented HaCaT cell apoptosis and induced activation of several molecular signaling pathways in keratinocytes. The data suggest that in cholesteatoma, HMGB1 released from stressed or necrotic epithelial cells and binding to RAGE overexpressed in keratinocytes initiates molecular signaling that culminates in pro-inflammatory cytokine release and chronic inflammation. Key message HMGB1 signaling engages multiple activation pathways in RAGE-positive keratinocytes. HMGB1 protects RAGE-positive keratinocytes from drug-induced apoptosis. Keratinocyte proliferation is controlled via RAGE and HMGB1 molecular signaling. Molecular signaling of the HMGB1/RAGE axis contributes to cholesteatoma pathogenesis.
    Journal of Molecular Medicine 11/2014; 93(3). DOI:10.1007/s00109-014-1217-3 · 5.11 Impact Factor
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    Chang Sook Hong · Laurent Muller · Michael Boyiadzis · Theresa L Whiteside
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    ABSTRACT: Exosomes are membrane-bound vesicles found in all biological fluids. AML patients' plasma collected at diagnosis contains elevated exosome levels relative to normal donor (ND) plasma. The molecular profile of AML exosomes changes in the course of therapy and may serve as a measure of disease progression or response to therapy. However, plasma contains a mix of exosomes derived from various cell types. To be able to utilize blast-derived exosomes as biomarkers for AML, we have developed an immunoaffinity-based capture method utilizing magnetic microbeads coated with anti-CD34 antibody (Ab). This Ab is specific for CD34, a unique marker of AML blasts. The capture procedure was developed using CD34+ exosomes derived from Kasumi-1 AML cell culture supernatants. The capture capacity of CD34microbeads was shown to linearly correlate with the input exosomes. A 10 uL aliquot of CD34 microbeads was able to capture all of CD34+ exosomes present in 100-1,000 uL of AML plasma. The levels of immunocaptured CD34+ exosomes correlated with the percentages of CD34+ blasts in the AML patients' peripheral blood. The immunocaptured exosomes had a typical cup-shaped morphology by transmission electron microscopy, and their molecular cargo was similar to that of parental blasts. These exosomes were biologically-active. Upon co-incubation with natural killer (NK) cells, captured blast-derived exosomes down-regulated surface NKG2D expression, while non-captured exosomes reduced expression levels of NKp46. Our data provide a proof-of-principle that blast-derived exosomes can be quantitatively recovered from AML patients' plasma, their molecular profile recapitulates that of autologous blasts and they retain the ability to mediate immune suppression. These data suggest that immunocaptured blast-derived exosomes might be useful in diagnosis and/or prognosis of AML in the future.
    PLoS ONE 08/2014; 9(8):e103310. DOI:10.1371/journal.pone.0103310 · 3.23 Impact Factor
  • Lisa H Butterfield · Theresa L Whiteside
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    ABSTRACT: In this article, we describe currently available methods for measuring NK cell functions: cytotoxicity and cytokine expression using flow cytometry-based assays and cytokine production using the Luminex-based technology. Quality control measures necessary for assay accuracy and reliability are also addressed.
    Critical reviews in oncogenesis 06/2014; 19(1-2):47-55.
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    ABSTRACT: Effects of exosomes present in human plasma on immune cells have not been examined in detail. Immunological studies with plasma-derived exosomes require their isolation by procedures involving ultracentrifugation. These procedures were largely developed using supernatants of cultured cells. To test biologic activities of plasma-derived exosomes, methods are necessary that ensure adequate recovery of exosome fractions free of contaminating larger vesicles, cell fragments and protein/nucleic acid aggregates. Here, an optimized method for exosome isolation from human plasma/serum specimens of normal controls (NC) or cancer patients and its advantages and pitfalls are described. To remove undesirable plasma-contaminating components, ultrafiltration of differentially-centrifuged plasma/serum followed by size-exclusion chromatography prior to ultracentrifugation facilitated the removal of contaminants. Plasma or serum was equally acceptable as a source of exosomes based on the recovered protein levels (in μg protein/mL plasma) and TEM image quality. Centrifugation on sucrose density gradients led to large exosome losses. Fresh plasma was the best source of morphologically-intact exosomes, while the use of frozen/thawed plasma decreased exosome purity but not their biologic activity. Treatments of frozen plasma with DNAse, RNAse or hyaluronidase did not improve exosome purity and are not recommended. Cancer patients' plasma consistently yielded more isolated exosomes than did NCs' plasma. Cancer patients' exosomes also mediated higher immune suppression as evidenced by decreased CD69 expression on responder CD4+ T effector cells. Thus, the described procedure yields biologically-active, morphologically-intact exosomes that have reasonably good purity without large protein losses and can be used for immunological, biomarker and other studies.
    Journal of Immunological Methods 06/2014; 411. DOI:10.1016/j.jim.2014.06.007 · 1.82 Impact Factor
  • Theresa L Whiteside
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    ABSTRACT: Introduction: Regulatory T cells (Tregs) accumulating in the peripheral circulation and tumor sites of patients contribute to tumor escape from the host immune system. Tregs encompass subsets of immune cells with distinct phenotypic and functional properties. Whereas natural (n) or thymic-derived (t) Tregs regulate responses to self-antigens, inducible (i) or peripheral (p) Tregs generated and expanded in regulatory microenvironments control immune responses to a broad variety of antigens. Areas covered: Tregs accumulating in the tumor microenvironment (TME) are contextually regulated. They acquire phenotypic and functional attributes imposed by the inhibitory molecular pathways operating in situ. Several molecular pathways active in human cancer are reviewed. The pathways may differ from one tumor to another, and environmentally induced Tregs may be functionally distinct. Potential therapeutic strategies for selective silencing of iTregs are considered in the light of the newly acquired understanding of their phenotypic and functional diversity. Expert opinion: Human Tregs accumulating in cancer comprise 'bad' subsets, which inhibit antitumor immunity, and 'good' anti-inflammatory subsets, which maintain tolerance to self and benefit the host. Future therapeutic strategies targeting Tregs will need to discriminate between these Treg subsets and will need to consider reprogramming strategies instead of Treg elimination. Re-establishment of effective antitumor immune responses in cancer patients without disturbing a normal homeostatic T-cell balance will greatly benefit from insights into inhibitory pathways engaged by human tumors.
    Expert Opinion on Biological Therapy 06/2014; 14(10):1-15. DOI:10.1517/14712598.2014.927432 · 3.74 Impact Factor
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    ABSTRACT: Purpose: Diffuse brainstem gliomas (BSGs) and other high-grade gliomas (HGGs) of childhood carry a dismal prognosis despite current treatments, and new therapies are needed. Having identified a series of glioma-associated antigens (GAAs) commonly overexpressed in pediatric gliomas, we initiated a pilot study of subcutaneous vaccinations with GAA epitope peptides in HLA-A2-positive children with newly diagnosed BSG and HGG. Patients and methods: GAAs were EphA2, interleukin-13 receptor alpha 2 (IL-13Rα2), and survivin, and their peptide epitopes were emulsified in Montanide-ISA-51 and given every 3 weeks with intramuscular polyinosinic-polycytidylic acid stabilized by lysine and carboxymethylcellulose for eight courses, followed by booster vaccinations every 6 weeks. Primary end points were safety and T-cell responses against vaccine-targeted GAA epitopes. Treatment response was evaluated clinically and by magnetic resonance imaging. Results: Twenty-six children were enrolled, 14 with newly diagnosed BSG treated with irradiation and 12 with newly diagnosed BSG or HGG treated with irradiation and concurrent chemotherapy. No dose-limiting non-CNS toxicity was encountered. Five children had symptomatic pseudoprogression, which responded to dexamethasone and was associated with prolonged survival. Only two patients had progressive disease during the first two vaccine courses; 19 had stable disease, two had partial responses, one had a minor response, and two had prolonged disease-free status after surgery. Enzyme-linked immunosorbent spot analysis in 21 children showed positive anti-GAA immune responses in 13: to IL-13Rα2 in 10, EphA2 in 11, and survivin in three. Conclusion: GAA peptide vaccination in children with gliomas is generally well tolerated and has preliminary evidence of immunologic and clinical responses. Careful monitoring and management of pseudoprogression is essential.
    Journal of Clinical Oncology 06/2014; 32(19). DOI:10.1200/JCO.2013.54.0526 · 18.43 Impact Factor

Publication Stats

22k Citations
3,057.63 Total Impact Points


  • 1975–2015
    • University of Pittsburgh
      • • Department of Otolaryngology
      • • Department of Pathology
      • • Pittsburgh Cancer Institute
      • • Department of Medicine
      • • Division of Clinical Immunopathology
      Pittsburgh, Pennsylvania, United States
  • 2009
    • Poznan University of Medical Sciences
      Posen, Greater Poland Voivodeship, Poland
  • 2003
    • Humboldt-Universität zu Berlin
      Berlín, Berlin, Germany
    • University of Louisville
      Louisville, Kentucky, United States
  • 1999–2002
    • Johannes Gutenberg-Universität Mainz
      Mayence, Rheinland-Pfalz, Germany
  • 2001
    • National Cancer Institute (USA)
      베서스다, Maryland, United States
    • Harvard Medical School
      • Department of Orthopaedic Surgery
      Boston, Massachusetts, United States
  • 2000
    • Kumamoto University
      • Center for AIDS Research
      Kumamoto-shi, Kumamoto Prefecture, Japan
  • 1997
    • University of Wisconsin–Madison
      • Department of Human Oncology
      Madison, Wisconsin, United States
  • 1996
    • Georgetown University
      Washington, Washington, D.C., United States
  • 1983–1994
    • Pittsburg State University
      Kansas, United States
  • 1993
    • Victor Babes National Institute of Pathology
      Bucureşti, Bucureşti, Romania
  • 1992
    • University of Zurich
      • Internal Medicine Unit
      Zürich, Zurich, Switzerland
  • 1990
    • Pittsburgh Institute of Aeronautics
      Pittsburgh, Pennsylvania, United States
    • Western Psychiatric Institute and Clinic
      Pittsburgh, Pennsylvania, United States
  • 1986–1988
    • Ludwig Institute for Cancer Research
      La Jolla, California, United States
    • Allegheny General Hospital
      Pittsburgh, Pennsylvania, United States