David T Curiel

Washington University in St. Louis, San Luis, Missouri, United States

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Publications (793)4229.41 Total impact

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    ABSTRACT: Bacillus anthracis, the causative agent of anthrax, secretes three polypeptides which form the bipartite lethal and edema toxins (LT, ET). The common component in these toxins, protective antigen (PA), is responsible for binding to cellular receptors and translocating the lethal factor (LF) and edema factor (EF) enzymatic moieties to the cytosol. Antibodies against PA protect against anthrax. We previously isolated toxin-neutralizing variable domains of camelid heavy-chain only antibodies (VHHs) and demonstrated their in vivo efficacy. In this work, gene therapy with an adenoviral vector (Ad/VNA2-PA) promoting expression of a bispecific VHH-based neutralizing agent (VNA2-PA) consisting of two linked VHHs targeting different PA neutralizing epitopes was tested in two inbred mouse strains, BALB/cJ and C57BL/6J, and found to protect mice against anthrax toxin challenge and anthrax spore infection. Two weeks after a single treatment with Ad/VNA2-PA, serum VNA2-PA levels remained above 1 μg/ml, with some as high as 10 mg/ml. Levels were 10-100 fold higher and persisted longer in C57BL/6J than in BALB/cJ mice. Mice were challenged with a lethal dose of LT or spores at various times after Ad/VNA2-PA administration. The majority of BALB/cJ mice having serum VNA2-PA levels >0.1 μg/ml survived LT challenge and 9 of 10 C57BL/6J mice with serum levels >1 μg/ml survived spore challenge. Our findings demonstrate the potential for genetic delivery of VNAs as an effective method for providing prophylactic protection from anthrax. We also extend prior findings of mouse strain-based differences in transgene expression and persistence by adenoviral vectors.
    No preview · Article · Jan 2016 · Clinical and vaccine Immunology: CVI
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    ABSTRACT: Studies have demonstrated that oncolytic adenoviruses based on a 24 base pair deletion in the viral E1A gene (D24) may be promising therapeutics for treating a number of cancer types. In order to increase the therapeutic potential of these oncolytic viruses, a novel conditionally replicating adenovirus targeting multiple receptors upregulated on tumors was generated by incorporating an Ad5/3 fiber with a carboxyl terminus RGD ligand. The virus displayed full cytopathic effect in all tumor lines assayed at low titers with improved cytotoxicity over Ad5-RGD D24, Ad5/3 D24 and an HSV oncolytic virus. The virus was then engineered to deliver immunotherapeutic agents such as GM-CSF while maintaining enhanced heterogenic oncolysis.
    Full-text · Article · Dec 2015 · PLoS ONE

  • No preview · Conference Paper · Oct 2015

  • No preview · Article · Aug 2015 · Cancer Research

  • No preview · Article · Aug 2015 · Cancer Research
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    ABSTRACT: The dismal clinical context of advanced-grade glioma demands the development of novel therapeutic strategies with direct patient impact. Adenovirus-mediated virotherapy represents a potentially effective approach for glioma therapy. In this research, we generated a novel glioma specific adenovirus by instituting more advanced genetic modifications which can maximize the efficiency and safety of therapeutic adenoviral vectors. In this regard, a glioma-specific targeted fiber was developed through the incorporation of previously published glioma-specific, phage-panned peptides (VWT peptide) on a fiber fibritin-based chimeric fiber, designated as 'GliomaFF.' We showed that the entry of this virus was highly restricted to glioma cells, supporting the specificity imparted by the phage-panned peptide. Additionally, the stability of the targeting moiety presented by fiber fibritin structure permitted greatly enhanced infectivity. Furthermore, the replication of this virus was restricted in glioma cells by controlling the expression of E1 gene under the activity of the tumor-specific survivin promoter. Utilizing this approach, we were able to explore the combinatorial efficacy of different adenoviral modifications that could amplify the specificity, infectivity, and exclusive replication of this therapeutic adenovirus in glioma. Finally, the virotherapy with this modified virus resulted in up to a 70% extended survival in an in vivo murine glioma model. These data demonstrate this novel adenoviral vector is a safe and efficient to treat this difficult malignancy.
    No preview · Article · May 2015 · Human gene therapy
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    M Beatty · L Timares · DT Curiel

    Full-text · Dataset · Apr 2015

  • No preview · Article · Apr 2015 · Gynecologic Oncology

  • No preview · Article · Apr 2015 · Gynecologic Oncology
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    ABSTRACT: The NAD(+)-dependent protein deacetylase SIRT1 regulates energy metabolism, responses to stress, and aging by deacetylating many different proteins, including histones and transcription factors. The mechanisms controlling SIRT1 enzymatic activity are complex and incompletely characterized, yet essential for understanding how to develop therapeutics that target SIRT1. Here, we demonstrate that the N-terminal domain of SIRT1 (NTERM) can trans-activate deacetylation activity by physically interacting with endogenous SIRT1 and promoting its association with the deacetylation substrate NF-κB p65. Two motifs within the NTERM domain contribute to activation of SIRT1-dependent activities, and expression of one of these motifs in mice is sufficient to lower fasting glucose levels and improve glucose tolerance in a manner similar to overexpression of SIRT1. Our results provide insights into the regulation of SIRT1 activity and a rationale for pharmacological control of SIRT1-dependent activities. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Full-text · Article · Mar 2015 · Cell Reports
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    M S Beatty · L Timares · DT Curiel
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    ABSTRACT: Adenoviruses are currently used in a variety of bench and bedside applications. However, their employment in gene delivery to lymphocyte lineages is hampered by the lack of coxsackie virus and adenovirus receptor (CAR) on the cell surface. Exploitation of an alternative receptor on the surface of T lymphocytes can allow for utilization of adenovirus in a variety of T lymphocyte-based diseases and therapies. Here, we describe how resistance to infection can be overcome by the utilization of a bi-specific fusion protein, soluble CAR murine interleukin 2 (sCAR-mIL-2), that retargets adenovirus to the murine IL-2 receptor (IL-2R). Infection of a murine T-cell line, CTLL-2, with a sCAR-mIL-2/Adenovirus conjugate provided a ninefold increase in both green fluorescence protein-positive cells and luciferase expression. In addition, this increase in infection was also seen in isolated primary murine T lymphocytes. In this context, the sCAR-mIL-2 adapter provided a fourfold gene transduction increase in activated primary murine T lymphocytes. Our results show that recombinant sCAR-mIL-2 fusion protein promotes IL-2R-targeted gene transfer to murine T lymphocytes and that alternative targeting can abrogate their native resistance to infection. Correction to: Cancer Gene Therapy (2013) 20, 445–452;doi:10.1038/cgt.2013.39; published online 9 August 2013
    Full-text · Article · Mar 2015 · Cancer gene therapy
  • W H Everett · D T Curiel
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    ABSTRACT: Radiation therapy is a critical component of cancer treatment with over half of patients receiving radiation during their treatment. Despite advances in image-guided therapy and dose fractionation, patients receiving radiation therapy are still at risk for side effects due to off-target radiation damage of normal tissues. To reduce normal tissue damage, researchers have sought radioprotectors, which are agents capable of protecting tissue against radiation by preventing radiation damage from occurring or by decreasing cell death in the presence of radiation damage. Although much early research focused on small-molecule radioprotectors, there has been a growing interest in gene therapy for radioprotection. The amenability of gene therapy vectors to targeting, as well as the flexibility of gene therapy to accomplish ablation or augmentation of biologically relevant genes, makes gene therapy an excellent strategy for radioprotection. Future improvements to vector targeting and delivery should greatly enhance radioprotection through gene therapy.Cancer Gene Therapy advance online publication, 27 February 2015; doi:10.1038/cgt.2015.8.
    No preview · Article · Feb 2015 · Cancer Gene Therapy
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    ABSTRACT: Conditionally replicative adenoviruses are promising agents for oncolytic virotherapy. Various approaches have been attempted to retarget adenoviruses to tumor-specific antigens to circumvent deficiency of receptor for adenoviral binding and to provide an additional level of tumor specificity. Functional incorporation of highly specific targeting molecules into the viral capsid can potentially retarget adenoviral infection. However, conventional antibodies are not compatible with the cytoplasmic adenovirus capsid synthesis. The goal of this study was to evaluate the utility of single variable domains derived from heavy chain camelid antibodies for retargeting of adenovirus infection. We have combined transcriptional targeting using a tumor-specific promoter with transductional targeting through viral capsid incorporation of antihuman carcinoembryonic antigen single variable domains. Obtained data demonstrated that employment of a single variable domain genetically incorporated into an adenovirus fiber increased specificity of infection and efficacy of replication of single variable domain-targeted oncolytic adenovirus. The double targeting, both transcriptional through the C-X-C chemokine receptor type 4 promoter and transductional using the single variable domain, is a promising means to improve the therapeutic index for these advanced generation conditionally replicative adenoviruses. A successful strategy to transductional retargeting of oncolytic adenovirus infection has not been shown before and therefore we believe this is the first employment of transductional targeting using single variable domains derived from heavy chain camelid antibodies to enhance specificity of conditionally replicative adenoviruses.
    Full-text · Article · Feb 2015
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    Full-text · Article · Jan 2015 · Toxicon
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    ABSTRACT: Purpose: We decided to construct a novel oncolytic adenovirus whose replication was driven by the CDC25B promoter for its use in preclinical models of pancreatic cancer. Experimental design: We placed the essential E1A gene under control of the CDC25B promoter. Based on preliminary data we pseudotyped the adenovirus with a chimeric fiber of serotypes 5/3. We investigated the in vitro lytic effect and the in vivo therapeutic efficacy in combination with gemcitabine, on human pancreatic tumor xenografts orthotopically growing in nude mice, and in tumors growing in Syrian hamsters. We also assessed biochemical markers of hepatic toxicity and CA19.9 levels. Results: AV25CDC exhibited a strong in vitro lytic effect on pancreatic cancer cells. In vivo administration of AV25CDC combined with gemcitabine in mice harboring s.c. growing SW1990 pancreatic tumors, almost abrogated tumor growth. Nude mice harboring 15-days old orthotopic tumors, treated i.t. or systemically with AV25CDC combined with gemcitabine, exhibited 70%-80% reduction in tumor size compared to control mice that lasted for at least 60 days. Chemo-virotherapy treatment induced a return to normal levels of biochemical parameters of hepatic toxicity; these mice exhibited more than 90% reduction in CA19.9 serum levels compared to control. Chemo-virotherapy efficacy was confirmed in mice harboring Mia PaCa-2 tumors and in Syrian hamster harboring HaP-T1 tumors. We observed that viral treatment disrupted tumor architecture and induced an increase in MMP-9 activity that might facilitate gemcitabine penetrability. Conclusions: These data demonstrates that AV25CDC is an effective oncolytic agent candidate for pancreatic cancer chemo-virotherapy combination. Copyright © 2015, American Association for Cancer Research.
    Full-text · Article · Jan 2015 · Clinical Cancer Research
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    ABSTRACT: Hemolytic uremic syndrome (HUS), caused by Shiga toxin-(Stx) produced by E. coli (STEC), remains untreatable. Human Stx monoclonal antibodies, which are highly effective in preventing Stx- sequelae in animal models, are languishing due to cost and logistics. We previously reported the production and evaluation of a camelid VHH-based neutralizing agent (VNA) targeting Stx1 and Stx2 (VNA-Stx), protected mice from Stx1 and Stx2 intoxications. Here we report that a single intramuscular (IM) injection of a non-replicating adenovirus (Ad) vector, carrying a secretory transgene of VNA-Stx (Ad/VNA-Stx), protected mice challenged with Stx2, and gnotobiotic piglets infected with STEC from fatal systemic intoxication. One IM dose of Ad/VNA-Stx virus given to piglets 24 hours after bacterial challenge prevented fatal central nervous system (CNS) symptoms in 9 of 10 animals, and in 5 of 9 when it was given 48 hours after bacterial challenge, just prior to the onset of CNS symptoms. All 6 placebo animals died or were euthanized with severe CNS symptoms. Ad/VNA-Stx treatment had no impact on the diarrhea. In conclusion, Ad/VNA-Stx treatment is effective in protecting piglets against Stx2-mediated fatal CNS complications following STEC challenge. With low production cost and further development, this could presumably be an effective treatment for patients with HUS and/or individuals with high risk of developing HUS due to exposure to STEC.
    Preview · Article · Nov 2014 · Infection and Immunity
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    ABSTRACT: An obstacle to effective gene-based cancer therapies is the limited number of cancer-specific growth suppressing and apoptosis-inducing genes. Using a differentiation induction subtraction hybridization (DISH) approach with human melanoma cells, melanoma differentiation associated (mda) genes were isolated that display elevated expression as a function of irreversible growth arrest, cancer reversion and terminal differentiation. This screening paradigm resulted in the cloning of mda-7 in the context of terminal differentiation of human melanoma cells. Based on its structure, chromosomal location, sequence homology and cytokine-like properties, mda-7 has now been renamed IL-24 and classified as a member of the expanding IL-10 cytokine gene family. Expression of mda-7/IL-24 inversely correlates with melanoma progression and administration of mda-7/IL-24 by means of a replication incompetent adenovirus, Ad.mda-7, results in growth suppression and apoptosis in melanoma cells as well as in a broad-spectrum of additional cancer cell types. In contrast, Ad.mda-7 does not elicit deleterious effects in normal cells, including those of epithelial, fibroblast, astrocyte, melanocyte or endothelial origin. Based on these distinctive properties and anti-tumor and anti-angiogenic activities in human tumor xenograft animal models, mda-7/IL-24 has now entered the clinical arena. A Phase I/II clinical trial in patients with advanced carcinomas involving intratumoral administration of mda-7/IL-24 [using a replication incompetent adenovirus; ING241 (Ad.mda-7)] has documented that this gene is safe and well tolerated by patients and a single virus injection elicits apoptosis in a majority of the tumor. Current data suggests that mda-7/IL-24 may function as a dual-acting cytokine in which its normal physiological functions may be related to specific aspects of the immune system and over-expression culminates in cancer-specific apoptosis. This review will provide a prospectus of our current understanding of mda-7/IL-24.
    No preview · Article · Oct 2014 · Cancer biology & therapy
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    ABSTRACT: Increased expression of sialyl Lewis(x/a) carbohydrates, ligands for E-selectin, correlates with clinically advanced stages and metastasis of gastric and colon cancers. In contrast, Sd(a) carbohydrate is abundantly detected in the normal gastrointestinal mucosa but dramatically reduced or lost in cancer tissues. A glycosyltransferase, β1,4N-acetylgalactosaminyltransferase 2 (B4GALNT2) that catalyzes Sd(a) carbohydrate synthesis, is silenced in cancer. In the present study, we aimed at reducing the expression of sialyl Lewis(x/a) of cancer cells in vivo by forced expression of B4GALNT2 and Sd(a), thereby preventing dissemination/metastasis, especially metastasis triggered by surgical maneuvers. We used a fiber-modified adenovirus (Ad) vector that contained a chimeric construct with a serotype 5 shaft and a serotype 3 knob. Using this Ad5/3 vector, we successfully introduced the B4GALNT2 gene into a human gastric cancer cell line KATO III in vitro and confirmed replacement of sialyl Lewis(x) to Sd(a) with a decrease in E-selectin-dependent adhesion. Administration of Ad5/3-B4GALNT2 vectors into the peritoneal cavity of mice after inoculation of KATO III cells with laparotomy significantly reduced the incidence of metastasis. Our results indicate that the transfer of a single gene encoding B4GALNT2 modified carbohydrate chains of cancer cells in vivo and decreased tumor dissemination and metastasis.Cancer Gene Therapy advance online publication, 12 September 2014; doi:10.1038/cgt.2014.46.
    Full-text · Article · Sep 2014 · Cancer Gene Therapy
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    ABSTRACT: AbstractA significant limiting factor to the human clinical application of conditionally replicative adenovirus (CRAd)-based virotherapy is the inability to noninvasively monitor these agents and their potential persistence. To address this issue, we proposed a novel imaging approach that combines transient expression of the human somatostatin receptor (SSTR) subtype 2 reporter gene with genetic labeling of the viral capsid with mCherry fluorescent protein. To test this dual modality system, we constructed the Ad5/3Δ24pIXcherry/SSTR CRAd and validated its capacity to generate fluorescent and nuclear signals in vitro and following intratumoral injection. Analysis of 64Cu-CB-TE2A-Y3-TATE biodistribution in mice revealed reduced uptake in tumors injected with the imaging CRAd relative to the replication-incompetent, Ad-expressing SSTR2 but significantly greater uptake compared to the negative CRAd control. Optical imaging demonstrated relative correlation of fluorescent signal with virus replication as determined by viral genome quantification in tumors. Positron emission tomography/computed tomography studies demonstrated that we can visualize radioactive uptake in tumors injected with imaging CRAd and the trend for greater uptake by standardized uptake value analysis compared to control CRAd. In the aggregate, the plasticity of our dual imaging approach should provide the technical basis for monitoring CRAd biodistribution and persistence in preclinical studies while offering potential utility for a range of clinical applications.
    No preview · Article · Sep 2014 · Molecular Imaging
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    ABSTRACT: Current therapies for most acute toxin exposures are limited to administration of polyclonal antitoxin serum. We have shown that VHH-based neutralizing agents (VNAs) consisting of two or more linked, toxin-neutralizing heavy-chain-only VH domains (VHHs), each binding distinct epitopes, can potently protect animals from lethality in several intoxication models including Botulinum neurotoxin serotype A1 (BoNT/A1). Appending a 14 amino acid albumin binding peptide (ABP) to an anti-BoNT/A1 heterodimeric VNA (H7/B5) substantially improved serum stability and resulted in an effective VNA serum half-life of 1 to 2 days. A recombinant, replication-incompetent, adenoviral vector (Ad/VNA-BoNTA) was engineered that induces secretion of biologically active VNA, H7/B5/ABP (VNA-BoNTA), from transduced cells. Mice administered a single dose of Ad/VNA-BoNTA, or a different Ad/VNA, via different administration routes led to a wide range of VNA serum levels measured four days later; generally intravenous > intraperitoneal > intramuscular > subcutaneous. Ad/VNA-BoNTA treated mice were 100% protected from 10 LD50 of BoNT/A1 for more than six weeks and protection positively correlated with serum levels of VNA-BoNTA exceeding about 5 ng/ml. Some mice developed antibodies that inhibited VNA binding to target but these mice displayed no evidence of kidney damage due to deposition of immune complexes. Mice were also successfully protected from 10 LD50 BoNT/A1 when Ad/VNA-BoNTA was administered up to 1.5 hours post-intoxication, demonstrating rapid appearance of the protective VNA in serum following treatment. Genetic delivery of VNAs promises to be an effective method of providing prophylactic protection and/or acute treatments for many toxin-mediated diseases.
    Full-text · Article · Aug 2014 · PLoS ONE

Publication Stats

30k Citations
4,229.41 Total Impact Points


  • 2011-2015
    • Washington University in St. Louis
      • Department of Radiation Oncology
      San Luis, Missouri, United States
  • 1994-2014
    • University of Alabama at Birmingham
      • • Department of Medicine
      • • Division of Gastroenterology & Hepatology
      • • Department of Surgery
      • • Comprehensive Cancer Center
      Birmingham, Alabama, United States
  • 2013
    • Washington State University
      پولمن، واشینگتن, Washington, United States
  • 2008-2009
    • Virginia Commonwealth University
      • Department of Biochemistry and Molecular Biology
      Richmond, VA, United States
  • 2007
    • Royal Adelaide Hospital
      • Department of Thoracic Medicine
      Tarndarnya, South Australia, Australia
    • Mayo Clinic - Rochester
      Рочестер, Minnesota, United States
  • 2004-2007
    • Columbia University
      New York, New York, United States
    • VU University Medical Center
      • Department of Orthopedic Surgery
      Amsterdam, North Holland, Netherlands
    • Hebrew University of Jerusalem
      Yerushalayim, Jerusalem, Israel
  • 2006
    • University of Groningen
      Groningen, Groningen, Netherlands
    • University of Chicago
      Chicago, Illinois, United States
  • 2001-2004
    • VU University Amsterdam
      • • Department of Orthopaedic Surgery
      • • Department of Medical Oncology
      Amsterdamo, North Holland, Netherlands
    • National Hospital Organization Kyushu Cancer Center
      Hukuoka, Fukuoka, Japan
    • University of Glasgow
      • School of Medicine
      Glasgow, Scotland, United Kingdom
  • 2003
    • University of Helsinki
      Helsinki, Uusimaa, Finland
    • University of Kuopio
      Kuopio, Eastern Finland Province, Finland
  • 2002-2003
    • Tulane University
      • Section of Hematology and Medical Oncology
      New Orleans, Louisiana, United States
    • Technische Universität München
      • Institut für Experimentelle Onkologie und Therapieforschung
      München, Bavaria, Germany
    • Netherlands Cancer Institute
      • Department of Urology
      Amsterdamo, North Holland, Netherlands
  • 2000
    • Universität Regensburg
      Ratisbon, Bavaria, Germany
  • 1994-2000
    • University of Alabama
      Tuscaloosa, Alabama, United States
  • 1995
    • University of Washington Seattle
      • Department of Medicine
      Seattle, Washington, United States
  • 1991-1993
    • University of North Carolina at Chapel Hill
      • Department of Medicine
      North Carolina, United States
  • 1992
    • Research Institute of Molecular Pathology
      Wien, Vienna, Austria
  • 1990
    • National Cancer Institute (USA)
      베서스다, Maryland, United States