Theresa L Whiteside

University of Pittsburgh, Pittsburgh, Pennsylvania, United States

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Publications (701)3092.7 Total impact

  • No preview · Article · Feb 2016 · Scientific Reports
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    ABSTRACT: The culmination of over a century's work to understand the role of the immune system in tumor control has led to the recent advances in cancer immunotherapies that have resulted in durable clinical responses in patients with a variety of malignancies. Cancer immunotherapies are rapidly changing traditional treatment paradigms and expanding the therapeutic landscape for cancer patients. However, despite the current success of these therapies, not all patients respond to immunotherapy and even those that do often experience toxicities. Thus, there is a growing need to identify predictive and prognostic biomarkers that enhance our understanding of the mechanisms underlying the complex interactions between the immune system and cancer. Therefore, the Society for Immunotherapy of Cancer (SITC) reconvened an Immune Biomarkers Task Force to review state of the art technologies, identify current hurdlers, and make recommendations for the field. As a product of this task force, Working Group 2 (WG2), consisting of international experts from academia and industry, assembled to identify and discuss promising technologies for biomarker discovery and validation. Thus, this WG2 consensus paper will focus on the current status of emerging biomarkers for immune checkpoint blockade therapy and discuss novel technologies as well as high dimensional data analysis platforms that will be pivotal for future biomarker research. In addition, this paper will include a brief overview of the current challenges with recommendations for future biomarker discovery.
    Full-text · Article · Jan 2016
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    ABSTRACT: Background: We report the results of a phase I/II, open label, single-arm, clinical trial to evaluate the safety and anti-HIV efficacy of an autologous dendritic cell (DC)-based HIV-1 vaccine loaded with autologous HIV-1-infected apoptotic cells. Methods: Antiretroviral therapy (ART)-naïve individuals were enrolled and viremia was suppressed on ART prior to receiving 4 doses of DC-based vaccine. Participants underwent treatment interruption 6 weeks after the 3(rd) vaccine dose. Plasma HIV-1 RNA 12 weeks after treatment interruption was compared to the pre-ART baseline. Results: The vaccine was safe and well-tolerated, but did not prevent viral rebound during treatment interruption. Vaccination resulted in a modest but significant decrease in plasma viremia from the pre-ART baseline (from 4.53 log10 cps/mL to 4.27 log10 cps/mL; p=0.05). Four of the ten participants had a greater than 0.70log10 increase in HIV-1 RNA in plasma following vaccination despite continuous ART. Single molecule sequencing of HIV-1 RNA in plasma pre- and post-vaccination revealed increases in G>A hypermutants in gag and pol after vaccination which suggests cytolysis of infected cells. Conclusion: A DC-apoptotic body-based therapeutic HIV vaccine was safe and induced T-cell activation and cytolysis, including HIV-1-infected cells in a subset of study participants.
    No preview · Article · Dec 2015 · The Journal of Infectious Diseases
  • Michael Boyiadzis · Chang-Sook Hong · Theresa L Whiteside

    No preview · Article · Nov 2015
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    Michael Boyiadzis · Chang-Sook Hong · Theresa L Whiteside

    Preview · Article · Nov 2015
  • Theresa L Whiteside

    No preview · Article · Sep 2015 · Journal of the National Cancer Institute
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    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.
    No preview · Article · Sep 2015 · Journal of Clinical Oncology
  • 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.
    No preview · Article · Aug 2015 · Expert Review of Molecular Diagnostics
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    Theresa Whiteside

    Preview · Article · Aug 2015
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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. Electronic supplementary material The online version of this article (doi:10.1007/s00262-015-1729-x) contains supplementary material, which is available to authorized users.
    Full-text · Article · Jun 2015 · Cancer Immunology and Immunotherapy
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    Michael Boyiadzis · Theresa L Whiteside · Steven Z Pavletic

    Preview · Article · Jun 2015 · Aging
  • 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.
    No preview · Article · Jun 2015 · Expert opinion on biological therapy
  • L. Muller · P. Simms · M. Nishimura · S. Watkins · T. Whiteside

    No preview · Article · May 2015 · Oral Oncology
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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.
    No preview · Article · Apr 2015 · OncoImmunology
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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.
    No preview · Article · Apr 2015 · Cancer Research
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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.
    No preview · Article · Mar 2015 · Head & Neck
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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.
    No preview · Article · Mar 2015 · OncoImmunology
  • 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.
    No preview · Article · Feb 2015 · Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics
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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.
    Preview · Article · Jan 2015 · Blood Reviews
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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.
    Full-text · Article · Dec 2014 · Oncotarget

Publication Stats

26k Citations
3,092.70 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
  • 2014
    • Philipps University of Marburg
      Marburg, Hesse, Germany
  • 2008
    • University of Colorado
      Denver, Colorado, United States
  • 2005
    • Heinrich-Heine-Universität Düsseldorf
      Düsseldorf, North Rhine-Westphalia, Germany
  • 2003
    • University of Louisville
      • Division of Gynecology Oncology
      Louisville, Kentucky, United States
    • Humboldt-Universität zu Berlin
      Berlín, Berlin, Germany
  • 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
  • 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
  • 1992
    • University of Zurich
      • Internal Medicine Unit
      Zürich, Zurich, Switzerland
  • 1990
    • Pittsburgh Institute of Aeronautics
      Pittsburgh, Pennsylvania, United States
  • 1986-1988
    • Ludwig Institute for Cancer Research
      La Jolla, California, United States
    • Allegheny General Hospital
      Pittsburgh, Pennsylvania, United States
  • 1978
    • Childrens Hospital of Pittsburgh
      Pittsburgh, Pennsylvania, United States