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Arthur M. Krieg - One of the best experts on this subject based on the ideXlab platform.
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Toll-Like Receptor 9 (TLR9) agonists in the treatment of cancer
Oncogene, 2008Co-Authors: Arthur M. KriegAbstract:Although still early in clinical development, agonists of Toll-Like Receptor 9 (TLR9) have demonstrated potential for the treatment of cancer. TLR9 agonists directly induce activation and maturation of plasmacytoid dendritic cells and enhance differentiation of B cells into antibody-secreting plasma cells. Preclinical and early clinical data support the use of TLR9 agonists in patients with solid tumors and hematologic malignancies. In preclinical studies, TLR9 agonists have shown activity not only as monotherapy, but also in combination with multiple other therapies, including vaccines, antibodies, cellular therapies, other immunotherapies, antiangiogenic agents, radiotherapy, cryotherapy and some chemotherapies. Phase I and II clinical trials have indicated that these agents have antitumor activity as single agents and enhance the development of antitumor T-cell responses when used as therapeutic vaccine adjuvants. The activity and safety of these novel anticancer agents are being explored in a wide range of tumor types as part of a variety of therapeutic strategies with the goal of harnessing the immune response to fight cancer.
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Therapeutic potential of Toll-Like Receptor 9 activation.
Nature Reviews Drug Discovery, 2006Co-Authors: Arthur M. KriegAbstract:The discovery of Toll-Like Receptors (TLRs) offers the possibility to treat diseases by stimulating immune functions in a targeted manner. Krieg reviews the potential of synthetic DNAs that activate TLR9 and are in clinical development in cancer, infectious disease and asthma/allergy. In the decade since the discovery that mouse B cells respond to certain unmethylated CpG dinucleotides in bacterial DNA, a specific Receptor for these 'CpG motifs' has been identified, Toll-Like Receptor 9 (TLR9), and a new approach to immunotherapy has moved into the clinic based on the use of synthetic oligodeoxynucleotides (ODN) as TLR9 agonists. This review highlights the current understanding of the mechanism of action of these CpG ODN, and provides an overview of the preclinical data and early human clinical trial results using these drugs to improve vaccines and treat cancer, infectious disease and allergy/asthma.
Ekambar R. Kandimalla - One of the best experts on this subject based on the ideXlab platform.
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Synthesis, purification, and characterization of immune-modulatory oligodeoxynucleotides that act as agonists of Toll-Like Receptor 9.
Methods of Molecular Biology, 2011Co-Authors: Mallikarjuna Putta, Dong Yu, Ekambar R. KandimallaAbstract:: Methods and protocols for automated synthesis and purification of immune modulatory oligonucleotides (IMOs), a novel class of Toll-Like Receptor 9 (TLR9) agonists, are described. IMOs containing two short identical sequences of 11-mers with phosphorothioate linkages can be synthesized in parallel synthetic strategy. A C3-linker that mimics the natural inter-nucleotide distance was commonly used for joining the two segments of IMOs. NittoPhase solid support bearing a symmetrical C3-linker (glycerol) and nucleoside-β-cyanoethyl-N,N-diisopropylphosphoramidites were used for IMO synthesis. The parallel synthesis was carried out in a 3'→ 5' direction with removal of the final dimethoxytrityl (DMT) protecting group. After synthesis, the IMO was cleaved and deprotected by treating with aqueous ammonia. The product was purified on anion-exchange HPLC, desalted, lyophilized, and characterized by anion-exchange HPLC, capillary gel electrophoresis, polyacrylamide gel electrophoresis, and MALDI-TOF mass spectral analysis.
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A Novel Toll-Like Receptor 9 Agonist Cooperates with Trastuzumab in Trastuzumab-Resistant Breast Tumors through Multiple Mechanisms of Action
Clinical Cancer Research, 2009Co-Authors: Vincenzo Damiano, T. Gelardi, Sonia Garofalo, Roberta De Rosa, Roberto Bianco, Rosa Caputo, G. Merola, Luigi Racioppi, Corrado Garbi, Ekambar R. KandimallaAbstract:Purpose: Resistance to anti-HER2 monoclonal antibody trastuzumab is a relevant issue in breast cancer patients. Among the mechanisms implicated in trastuzumab resistance, increasing evidence supports a role of tumor microenvironment. We previously found that a novel Toll-Like Receptor 9 agonist, referred to as immune modulatory oligonucleotide (IMO) and currently under clinical investigation, acts through epidermal growth factor Receptor (EGFR) and shows direct antiangiogenic effects by cooperating with anti-EGFR or anti-VEGF drugs, thus interfering with cancer cells and microenvironment. Experimental Design: In this study, we used KPL-4 and JIMT-1 trastuzumab-resistant breast cancer cells to evaluate the combination IMO plus trastuzumab as a therapeutic option for trastuzumab-resistant breast cancers. Results: IMO inhibits KPL-4 and JIMT-1 xenografts growth and potentiates trastuzumab antitumor effect, with complete suppression of tumor growth, potent enhancement of trastuzumab-mediated antibody-dependent cell-mediated cytotoxicity, and strong inhibition of EGFR/HER2-related signaling. In KPL-4 xenografts, IMO alone interferes with HER signal transduction, whereas trastuzumab is ineffective. IMO induces an HER-dependent signal inhibition also in vitro by modulating a functional interaction between Toll-Like Receptor 9 and HER Receptors occurring at membrane level. Finally, IMO plus trastuzumab produces a cooperative antiangiogenic effect related to suppression of endothelial HER-related signaling. Conclusions: We showed a cooperative effect of IMO plus trastuzumab in trastuzumab-resistant breast cancers due to IMO direct antitumor and antiangiogenic activity and antibody-dependent cell-mediated cytotoxicity enhancement. Moreover, we provided first evidence of a Toll-Like Receptor 9/HER interaction at membrane level as novel mechanism of action. Altogether, we propose IMO plus trastuzumab as an effective strategy in trastuzumab-resistant breast cancers. (Clin Cancer Res 2009;15(22):6921–30)
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Agonists of Toll-Like Receptor 9 containing synthetic dinucleotide motifs.
Journal of Medicinal Chemistry, 2007Co-Authors: Dong Yu, Ekambar R. Kandimalla, Mallikarjuna Putta, Lakshmi Bhagat, Yukui Li, Daqing Wang, Jimmy X. Tang, Sudhir AgrawalAbstract:Oligodeoxynucleotides (ODNs) containing unmethylated CpG motifs activate Toll-Like Receptor 9 (TLR9). Our previous studies have shown that ODNs containing two 5′-ends are more immunostimulatory than those with one 5′-end. In the present study, to understand the role of functional groups in TLR9 recognition and subsequent immune response, we substituted C or G of a CpG dinucleotide with 5-OH-dC, 5-propyne-dC, furano-dT, 1-(2′-deoxy-β-d-ribofuranosyl)-2-oxo-7-deaza-8-methyl-purine, dF, 4-thio-dU, N3-Me-dC, N4-Et-dC, Ψ-iso-dC, and arabinoC or 7-deaza-dG, 7-deaza-8-aza-dG, 9-deaza-dG, N1-Me-dG, N2-Me-dG, 6-Thio-dG, dI, 8-OMe-dG, 8-O-allyl-dG, and arabinoG in ODN containing two 5′-ends. Agonists of TLR9 containing cytosine or guanine modification showed activity in HEK293 cells expressing TLR9, mouse spleen, and human cell-based assays and in vivo in mice. The results presented here provide insight into which specific chemical modifications at C or G of the CpG motif are recognized by TLR9 and the ability to m...
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Oral administration of a synthetic agonist of Toll-Like Receptor 9 potently modulates peanut-induced allergy in mice.
The Journal of Allergy and Clinical Immunology, 2007Co-Authors: Ekambar R. Kandimalla, Dong Yu, Sudhir AgrawalAbstract:Background Agonists of Toll-Like Receptor 9 have been shown to induce potent T H 1-type immune responses and prevent and reverse ovalbumin-induced T H 2-dominant allergic asthma in mice. Objective We examined oral administration of a synthetic agonist of Toll-Like Receptor 9 (immune modulatory oligonucleotide [IMO]) to modulate peanut-induced allergy in mice. Methods In the prevention model mice were sensitized 3 times by means of oral administration of peanut in the presence or absence of IMO. In a treatment protocol mice were sensitized orally with peanut on days 0 and 14 and treated 4 times with oral administration of IMO starting on day 21. Results In the prevention study mice that received the combination of IMO/peanut showed decreased IgE and increased IgG2a levels in the serum and intestinal tissue compared with mice sensitized with peanut only. In spleen cell recall experiments, production of IL-5 and IL-13 was inhibited and production of IFN-γ was increased in mice immunized with the peanut/IMO combination compared with those sensitized with peanut only. In the treatment model IMO-treated mice showed decreased IgE, IL-5, and IL-13 levels and increased IgG2a and IFN-γ levels in the serum, intestines, and spleen cells compared with PBS-treated mice. A reduction in local inflammation and restoration of normal structure in the intestines was found in the mice that received IMO in both models. Conclusion These results indicate that IMOs can switch peanut-induced T H 2 immune responses toward T H 1 responses accompanied by reduced inflammation in the gastrointestinal tract and anaphylaxis in both the prevention and treatment models. Clinical implications IMOs might be suitable candidates for the management of peanut-induced allergy.
Katri S. Selander - One of the best experts on this subject based on the ideXlab platform.
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Toll-Like Receptor 9 mediates invasion and predicts prognosis in squamous cell carcinoma of the mobile tongue.
Journal of Oral Pathology & Medicine, 2014Co-Authors: Joonas H. Kauppila, Katri S. Selander, Johanna Korvala, Kristiina Siirilä, Marika Manni, Laura K. Mäkinen, Jaana Hagström, Timo Atula, Caj Haglund, Juha SaarnioAbstract:Anatomy and Cell biology, University of Oulu, Oulu, FinlandBACKGROUND: Toll-Like Receptor 9 (TLR9) is a cellularReceptor, which recognizes bacterial and host-derivedDNA. Stimulation of TLR9 induces cellular invasion viamatrix metalloproteinase 13 (MMP-13). The aim of thisstudy was to evaluate the role of TLR9 in invasion of oraltongue squamous cell carcinoma (OTSCC).METHODS: The effects of TLR9 ligands on oral squa-mous cell carcinoma cell lines were studied with invasionand migration assays, as well as in a myoma organotypicmodel.RESULTS: The TLR9 ligand, CpG-ODN, increased inva-sion and migration in OTSCC lines. These effects werereduced by TLR9 siRNA or inhibition with TLR9antibodies. Immunohistochemical analysis of tissuesfrom 195 patients with OTSCC revealed that TLR9was expressed in 181/195 carcinomas. The expression ofTLR9 was higher in the malignant cells than in thenormal epithelium. High TLR9 expression was associ-ated with high MMP-13 expression and poor differenti-ation. High TLR9 expression was also identified as anindependent predictor of poor prognosis (HR 1.810,95% CI [1.053–3.112]).CONCLUSION: Toll-Like Receptor 9 mediates OTSCCinvasion and migration in vitro and is an independentprognostic factor of OTSCC. Inhibition of TLR9 may be anovel therapeutic opportunity in oral cancer.J Oral Pathol Med (2014)Keywords: invasion; matrix metalloproteinase 13; migration;Toll-Like Receptor 9; tongue cancer
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Toll-Like Receptor 9 in breast cancer.
Frontiers in Immunology, 2014Co-Authors: Jouko Sandholm, Katri S. SelanderAbstract:Toll-Like Receptor 9 (TLR9) is a cellular DNA Receptor of the innate immune system. DNA recognition via TLR9 results in an inflammatory reaction, which eventually also activates a Th1-biased adaptive immune attack. In addition to cells of the immune system, TLR9 mRNA and protein is also widely expressed in breast cancer cell lines and in clinical breast cancer specimens. Although synthetic TLR9-ligands induce cancer cell invasion in vitro, the role of TLR9 in cancer pathophysiology has remained unclear. In the studies conducted so far, tumor TLR9 expression has been shown to have prognostic significance only in patients that have triple negative breast cancer (TNBC). Specifically, high tumor TLR9 expression predicts good prognosis among TNBC patients. Pre-clinical studies suggest that TLR9 expression may affect tumor immunophenotype and contribute to the immunogenic benefit of chemotherapy. In this review, we discuss the possible contribution of tumor TLR9 to the pathogenesis and treatment responses in breast cancer.
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Increased Toll-Like Receptor 9 expression indicates adverse prognosis in oesophageal adenocarcinoma.
Histopathology, 2011Co-Authors: Joonas H. Kauppila, Heikki Takala, Katri S. Selander, Petri Lehenkari, Juha Saarnio, Tuomo J. KarttunenAbstract:Kauppila J H, Takala H, Selander K S, Lehenkari P P, Saarnio J & Karttunen T J (2011) Histopathology59, 643–649 Increased Toll-Like Receptor 9 expression indicates adverse prognosis in oesophageal adenocarcinoma Aims: Toll-Like Receptor 9 (TLR-9) is a cellular DNA Receptor that has been linked previously to invasion in various cancers. The aim of this study was to investigate TLR-9 expression and its possible association with prognosis in oesophageal adenocarcinoma. Methods and results: Immunohistochemical TLR-9 expression was graded in clinical specimens (n = 76) of oesophageal adenocarcinoma. The TLR-9 immunostaining intensity was compared with tumour grade, stage and indicators of proliferation, apoptosis and tumour vascular supply. High TLR-9 expression correlated with advanced tumour stage, tumour unresectability, poor differentiation and high proliferation. Strong immunoreactivity of TLR-9 also indicated poor overall survival. Conclusions: High TLR-9 expression is associated with poor differentiation, a high proliferation rate and disseminated disease. Accordingly, increased TLR-9 expression may contribute to the growth and metastatic properties of oesophageal adenocarcinoma.
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Toll-Like Receptor 9 is a novel biomarker for esophageal squamous cell dysplasia and squamous cell carcinoma progression.
Journal of Innate Immunity, 2011Co-Authors: Heikki Takala, Joonas H. Kauppila, Katri S. Selander, Petri Lehenkari, Juha Saarnio, Katri S. Vuopala, Ylermi Soini, Tuomo J. KarttunenAbstract:Background: Stimulation of Toll-Like Receptor 9 (TLR9) has been linked to invasion in various cancer cells in vitro. We investigated TLR9 expression in normal, dysplastic and malign
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Toll-Like Receptor-9 Expression Is Inversely Correlated with Estrogen Receptor Status in Breast Cancer
Journal of Innate Immunity, 2008Co-Authors: Arja Jukkola-vuorinen, Petri Lehenkari, Eeva Rahko, Katri S. Vuopala, Renee A. Desmond, Kevin W. Harris, Katri S. SelanderAbstract:Toll-Like Receptor 9 (TLR9) recognizes microbial and vertebrate DNA. We previously demonstrated TLR9 expression in human breast cancer cell lines and showed that TLR9 ligands stimulate their in vitro
Vivette D Dagati - One of the best experts on this subject based on the ideXlab platform.
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intestinal toll like Receptor 9 deficiency leads to paneth cell hyperplasia and exacerbates kidney intestine and liver injury after ischemia reperfusion injury
Kidney International, 2019Co-Authors: Hongmei Li, Vivette D DagatiAbstract:Intestinal Paneth cells play a critical role in ischemic acute kidney injury (AKI) by releasing interleukin 17A (IL-17A). Because Toll-Like Receptor 9 (TLR9) activation degranulates Paneth cells and necrotic tubular epithelial cells release several damage associated molecular patterns that target TLR9, we tested the hypothesis that intestinal TLR9 deficiency would protect against ischemic AKI and associated remote intestinal and hepatic dysfunction by decreasing Paneth cell degranulation. We generated mice lacking TLR9 in intestinal epithelia (TLR9fl/fl Villin Cre mice) and compared them to wild type (TLR9fl/fl) mice following right nephrectomy and left ischemia/reperfusion. To our surprise, mice lacking intestinal TLR9 had exacerbated kidney, liver, and small intestine injury after ischemia/reperfusion compared to wild type mice, characterized by increased kidney and intestinal inflammation, apoptosis, and necrosis as well as increased hepatic inflammation and apoptosis. Mice lacking intestinal TLR9 had larger Paneth cell granule size, pronounced intestinal macrophage infiltration, and higher intestinal crypt IL-17A expression. Administration of IL-17A neutralizing antibody prevented the exacerbation of ischemic AKI in mice lacking intestinal TLR9. These studies suggest that intestinal TLR9 activation protects against ischemic AKI and associated remote multi-organ dysfunction syndrome by regulating Paneth cell IL-17A synthesis.
Vincenzo Damiano - One of the best experts on this subject based on the ideXlab platform.
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Combination of a Toll-Like Receptor 9 agonist with everolimus interferes with the growth and angiogenic activity of renal cell carcinoma.
OncoImmunology, 2013Co-Authors: Roberta De Rosa, Vincenzo Damiano, Luigi Formisano, Lucia Nappi, Roberta Marciano, Bianca Maria Veneziani, Sabino De Placido, Roberto BiancoAbstract:The mTOR inhibitor everolimus is currently approved for the treatment of renal cell carcinoma (RCC) and several Toll-Like Receptor 9 (TLR9) agonists, including immunomodulatory oligonucleotides (IMOs), have been tested for their therapeutic potential against advanced RCC. However, no clinical trials investigating the combination of mTOR inhibitors with TLR9 agonists in RCC patients have been performed to date. Our results may pave the way to translate this combinatorial approach to the clinical setting.
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Toll-Like Receptor 9 agonist IMO cooperates with everolimus in renal cell carcinoma by interfering with tumour growth and angiogenesis
British Journal of Cancer, 2013Co-Authors: Vincenzo Damiano, R. Rosa, Luigi Formisano, Lucia Nappi, T. Gelardi, Roberta Marciano, Immacolata Cozzolino, Giancarlo Troncone, Sudhir Agrawal, Bianca Maria VenezianiAbstract:Toll-Like Receptor 9 agonist IMO cooperates with everolimus in renal cell carcinoma by interfering with tumour growth and angiogenesis
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A Novel Toll-Like Receptor 9 Agonist Cooperates with Trastuzumab in Trastuzumab-Resistant Breast Tumors through Multiple Mechanisms of Action
Clinical Cancer Research, 2009Co-Authors: Vincenzo Damiano, T. Gelardi, Sonia Garofalo, Roberta De Rosa, Roberto Bianco, Rosa Caputo, G. Merola, Luigi Racioppi, Corrado Garbi, Ekambar R. KandimallaAbstract:Purpose: Resistance to anti-HER2 monoclonal antibody trastuzumab is a relevant issue in breast cancer patients. Among the mechanisms implicated in trastuzumab resistance, increasing evidence supports a role of tumor microenvironment. We previously found that a novel Toll-Like Receptor 9 agonist, referred to as immune modulatory oligonucleotide (IMO) and currently under clinical investigation, acts through epidermal growth factor Receptor (EGFR) and shows direct antiangiogenic effects by cooperating with anti-EGFR or anti-VEGF drugs, thus interfering with cancer cells and microenvironment. Experimental Design: In this study, we used KPL-4 and JIMT-1 trastuzumab-resistant breast cancer cells to evaluate the combination IMO plus trastuzumab as a therapeutic option for trastuzumab-resistant breast cancers. Results: IMO inhibits KPL-4 and JIMT-1 xenografts growth and potentiates trastuzumab antitumor effect, with complete suppression of tumor growth, potent enhancement of trastuzumab-mediated antibody-dependent cell-mediated cytotoxicity, and strong inhibition of EGFR/HER2-related signaling. In KPL-4 xenografts, IMO alone interferes with HER signal transduction, whereas trastuzumab is ineffective. IMO induces an HER-dependent signal inhibition also in vitro by modulating a functional interaction between Toll-Like Receptor 9 and HER Receptors occurring at membrane level. Finally, IMO plus trastuzumab produces a cooperative antiangiogenic effect related to suppression of endothelial HER-related signaling. Conclusions: We showed a cooperative effect of IMO plus trastuzumab in trastuzumab-resistant breast cancers due to IMO direct antitumor and antiangiogenic activity and antibody-dependent cell-mediated cytotoxicity enhancement. Moreover, we provided first evidence of a Toll-Like Receptor 9/HER interaction at membrane level as novel mechanism of action. Altogether, we propose IMO plus trastuzumab as an effective strategy in trastuzumab-resistant breast cancers. (Clin Cancer Res 2009;15(22):6921–30)
