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toll like receptors and renal cell carcinoma

Nadeeka H De Silva, Takashi Akazawa, Viskam Wijewardana, Norimitsu Inoue, Maremichi Oyamada, Atsuko Ohta, Yuki Tachibana, Daluthgamage Patsy H Wijesekera, Mitsuru Kuwamura, Yasuko Nishizawa, Kazuyuki Itoh, Takeshi Izawa, Shingo Hatoya, Tetsuya Hasegawa, Jyoji Yamate, Toshio Inaba, Kikuya Sugiura
Although dendritic cell (DC)-based immunotherapy shows little toxicity, improvements should be necessary to obtain satisfactory clinical outcome. Using interferon-gamma injection along with DCs, we previously obtained significant clinical responses against small or early stage malignant tumors in dogs. However, improvement was necessary to be effective to largely developed or metastatic tumors. To obtain effective methods applicable to those tumors, we herein used a DC-targeting Toll-like receptor ligand, h11c, and examined the therapeutic effects in murine subcutaneous and visceral tumor models and also in the clinical treatment of canine cancers...
2017: PloS One
David Lynch, Adrian Murphy
Modulation of the interaction between the immune system and the tumor microenvironment has long been a target of cancer research, including colorectal cancer (CRC). Approaches explored to date include vaccines (autologous, peptide, dendritic cell, viral and bacterial), cytokine therapy, toll-like receptors (TLRs), autologous cell therapy and checkpoint inhibition. Until recently these approaches have been shown to have only modest efficacy in reducing tumor burden. However, significant breakthroughs have been made, with the use of checkpoint inhibitors targeting programmed cell death protein-1 (PD-1), programmed cell death ligand-1 (PD-L1), and cytotoxic T lymphocyte antigen-4 (CTLA-4)...
August 2016: Annals of Translational Medicine
Barbara Volz, Manuel Schmidt, Kerstin Heinrich, Kerstin Kapp, Matthias Schroff, Burghardt Wittig
The tumor vaccine MGN1601 was designed and developed for treatment of metastatic renal cell carcinoma (mRCC). MGN1601 consists of a combination of fourfold gene-modified cells with the toll-like receptor 9 agonist dSLIM, a powerful connector of innate and adaptive immunity. Vaccine cells originate from a renal cell carcinoma cell line (grown from renal cell carcinoma tissue), express a variety of known tumor-associated antigens (TAA), and are gene modified to transiently express two co-stimulatory molecules, CD80 and CD154, and two cytokines, GM-CSF and IL-7, aimed to support immune response...
2016: Molecular Therapy Oncolytics
Mikko Mella, Joonas H Kauppila, Peeter Karihtala, Petri Lehenkari, Arja Jukkola-Vuorinen, Ylermi Soini, Päivi Auvinen, Markku H Vaarala, Hanna Ronkainen, Saila Kauppila, Kirsi-Maria Haapasaari, Katri S Vuopala, Katri S Selander
Toll-like receptor 9 (TLR9) is a cellular DNA-receptor of the innate immune system that is widely expressed in cancers. We demonstrated that low tumor TLR9 expression predicts poor disease-specific survival in triple negative breast cancer (TNBC) and renal cell carcinoma (RCC). We hypothesized that this is because TLR9 expression affects tumor immunophenotype. To begin to test this, we compared the number of tumor infiltrating CD8(+) T lymphocytes with TLR9 expression in treatment naïve breast cancer (n = 197) and RCC (n = 94) cohorts with known TLR9 expression status...
June 2015: Oncoimmunology
Annkristin Heine, Stefanie Andrea Erika Held, Solveig Nora Daecke, Kati Riethausen, Philipp Kotthoff, Chrystel Flores, Christian Kurts, Peter Brossart
Inhibitors of VEGF receptor (VEGFR) signaling such as sorafenib and sunitinib that are currently used in the treatment of malignant diseases have been shown to affect immunological responses by inhibition of the function of antigen presenting cells and T lymphocytes. The VEGFR-inhibitor axitinib has recently been approved for second line therapy of metastatic renal cell carcinoma. While there is some evidence that axitinib might interfere with the activation of T cells, not much is known about the effects of axitinib on dendritic cell (DC) phenotype and function...
2015: PloS One
Roberta Rosa, Vincenzo Damiano, Luigi Formisano, Lucia Nappi, Roberta Marciano, Bianca Maria Veneziani, Sabino De Placido, Roberto Bianco
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.
August 1, 2013: Oncoimmunology
Le Xu, Junying Zheng, David H Nguyen, Quang T Luong, Gang Zeng
NY-ESO-1 is a cancer/germline antigen (Ag) with distinctively strong immunogenicity. We have previously demonstrated that NY-ESO-1 serves as an endogenous adjuvant by engaging dendritic cell (DC)-surface receptors of calreticulin (CRT) and toll-like receptor (TLR) 4. In the present study, NY-ESO-1 was investigated for its immunomodulatory roles as a molecular adjuvant in whole-tumor cell vaccines using the Renca kidney cancer model. Renca cells were genetically engineered to express NY-ESO-1 on the cell surface to enhance direct interactions with DC...
October 2013: Journal of Immunotherapy
James H Finke, Pat A Rayman, Jennifer S Ko, Judy M Bradley, Sandra J Gendler, Peter A Cohen
To move forward with immunotherapy, it is important to understand how the tumor microenvironment generates systemic immunosuppression in patients with renal cell carcinoma (RCC) as well as in patients with other types of solid tumors. Even though antigen discovery in RCC has lagged behind melanoma, recent clinical trials have finally authenticated that RCC is susceptible to vaccine-based therapy. Furthermore, judicious coadministration of cytokines and chemotherapy can potentiate therapeutic responses to vaccine in RCC and prolong survival, as has already proved possible for melanoma...
July 2013: Cancer Journal
V Damiano, R Rosa, L Formisano, L Nappi, T Gelardi, R Marciano, I Cozzolino, G Troncone, S Agrawal, B M Veneziani, S De Placido, R Bianco, G Tortora
BACKGROUND: Targeting the mammalian target of rapamycin by everolimus is a successful approach for renal cell carcinoma (RCC) therapy. The Toll-like receptor 9 agonist immune modulatory oligonucleotide (IMO) exhibits direct antitumour and antiangiogenic activity and cooperates with both epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) inhibitors. METHODS: We tested the combination of IMO and everolimus on models of human RCC with different Von-Hippel Lindau (VHL) gene status, both in vitro and in nude mice...
April 30, 2013: British Journal of Cancer
B Escudier
In recent years, an improved understanding of renal cell carcinoma (RCC) tumour biology has resulted in major advances in the treatment of patients with metastatic RCC (mRCC). Although immunotherapy with interleukin-2 and interferon-α was once the standard of care for mRCC, the introduction of novel agents targeting angiogenesis and signal transduction pathways has markedly improved patient outcomes. However, targeted agents rarely induce complete responses, and patients eventually develop resistance to therapy, prompting consideration of novel therapeutic approaches and a resurgence of interest in immunotherapy for RCC...
September 2012: Annals of Oncology: Official Journal of the European Society for Medical Oncology
Eric C Kauffman, Huixian Liu, Michael J Schwartz, Douglas S Scherr
Imidazoquinolines are synthetic toll-like receptor 7 and 8 agonists and potent dendritic cell activators with established anticancer activity. Here we test the hypothesis that imidazoquinoline has in vivo efficacy within established renal cell carcinoma (RCC) tumors. Immunocompetent mice bearing syngeneic RCC xenografts were treated with imidazoquinoline or placebo at two separate time points. Harvested tumors were assayed by TUNEL/caspase-3/Ki67 immunostains to evaluate cell death/apoptosis/proliferation, and CD3/B220/CD45 immunostains to evaluate T-cell lymphocyte/B-cell lymphocyte/pan-leukocyte tumor infiltration...
2012: Journal of Oncology
Tim Chan, Timothy C Back, Jeffrey J Subleski, Jonathan M Weiss, John R Ortaldo, Robert H Wiltrout
The liver is an immunologically unique organ containing tolerogenic dendritic cells (DC) that maintain an immunosuppressive microenvironment. Although systemic IL-12 administration can improve responses to tumors, the effects of IL-12-based treatments on DC, in particular hepatic DC, remain incompletely understood. In this study, we demonstrate systemic IL-12 administration induces a 2-3 fold increase in conventional, but not plasmacytoid, DC subsets in the liver. Following IL-12 administration, hepatic DC became more phenotypically and functionally mature, resembling the function of splenic DC, but differed as compared to their splenic counterparts in the production of IL-12 following co-stimulation with toll-like receptor (TLR) agonists...
2012: PloS One
Hanna Ronkainen, Pasi Hirvikoski, Saila Kauppila, Katri S Vuopala, Timo K Paavonen, Katri S Selander, Markku H Vaarala
BACKGROUND: Toll-like receptor 9 (TLR9) is a cellular DNA-receptor whose activation with cognate ligands triggers an immune reaction, with increased production of inflammatory cytokines. The aim of this study was to examine the expression of TLR9 in renal cell carcinoma (RCC), which is generally renowned of its immunogenic nature. We also evaluated the prognostic value of TLR9 in RCC. METHODS: TLR9 expression in RCC was characterized with immunohistochemistry in a retrospective study population of 152 RCC patients who underwent renal surgery...
2011: Journal of Experimental & Clinical Cancer Research: CR
Hui Yu, Shan-Shan Xu, Qin-Quan Cheng, Li-Mei He, Zhi Li
OBJECTIVE: To investigate the expression of toll-like receptors (TLR1-TLR10) in human renal carcinoma cell 786-0 and normal renal cell HK-2 and discuss the significance of TLRs in the development of renal carcinoma. METHODS: Human renal carcinoma cell 786-0 (experimental group) and normal renal cell HK-2 (control group) were cultured. The expression of TLR1-TLR10 was detected by real-time fluorogenic quantitative PCR (FQ-PCR). RESULTS: The FQ-PCR analysis demonstrated that 786-0 cell line and HK-2 cell line expressed TLR1-TLR6 and TLR8-TLR10 mRNA...
January 11, 2011: Zhonghua Yi Xue za Zhi [Chinese medical journal]
Yanal M Murad, Timothy M Clay
Toll-like receptors (TLRs) are part of the innate immune system, and they belong to the pattern recognition receptors (PRR) family. The PRR family is designed to recognize and bind conserved pathogen-associated molecular patterns, which are not generated by the host and are restricted and essential to micro-organisms. TLR9, which recognizes unmethylated CpG (cytosine guanosine dinucleotide), is a very promising target for therapeutic activation. Stimulation of TLR9 activates human plasmacytoid dendritic cells and B cells, and results in potent T helper-1 (T(h)1)-type immune responses and antitumor responses in mouse tumor models and in patients...
2009: BioDrugs: Clinical Immunotherapeutics, Biopharmaceuticals and Gene Therapy
John A Thompson, Timothy Kuzel, Beverly J Drucker, Walter J Urba, Ronald M Bukowski
PURPOSE: Single-agent PF-3512676 (agatolimod), a Toll-like receptor 9 agonist, was examined in an open-label, single-arm, multicenter phase I/II study to determine its maximum tolerated dose (MTD), safety profile, antitumor activity, pharmacokinetics, and immunologic effects in patients with advanced metastatic renal cell carcinoma (RCC). PATIENTS AND METHODS: PF-3512676 was administered subcutaneously weekly for up to 24 weeks to 39 adults with stage IV RCC. Patients were excluded if they had received previous therapy other than surgery...
October 2009: Clinical Genitourinary Cancer
Michael J Schwartz, Huixian Liu, David H Hwang, Hideki Kawamoto, Douglas S Scherr
OBJECTIVES: To evaluate the effects of imidazoquinolines in renal cell carcinoma (RCC). METHODS: In vitro experiments were carried out using mouse (RENCA) and human (CAKI-1, CAKI-2, and A-498) RCC cell lines. Toll-like receptor-7 (TLR7) expression was assessed by Western blot. We determined the ability of imidazoquinolines to induce apoptosis and inhibit cell viability in vitro. For in vivo experiments, RENCA cells were injected into the tail vein of syngeneic mice...
May 2009: Urology
J Kwon, J Park, D Lee, Y S Kim, H J Jeong
Toll-like receptor (TLR) is known to be a mediator of innate immunity, but recent reports have shown that TLR provides a link to adaptive immunity involved in allograft rejection. To explore the expression patterns in various conditions of renal transplantation, we examined TLR subunit mRNA expressions in renal allograft biopsies of acute rejection (AR; n = 11), chronic rejection (CR; n = 15), chronic cyclosporine nephrotoxicity (CsAN; n = 22), and immunoglobulin A nephropathy (IgAN; n = 9) patients. Control tissues (n = 7) were obtained from normal renal cortical tissue of renal cell carcinoma patients...
December 2008: Transplantation Proceedings
Teppei Morikawa, Akira Sugiyama, Haruki Kume, Satoshi Ota, Takeshi Kashima, Kyoichi Tomita, Tadaichi Kitamura, Tatsuhiko Kodama, Masashi Fukayama, Hiroyuki Aburatani
PURPOSE: Renal cell carcinoma (RCC) is one of the most drug-refractory cancers. The aim of this study is to discover a novel therapeutic target molecule for clear cell RCC (CCRCC), which accounts for the majority of RCC. EXPERIMENTAL DESIGN: Gene expression profiles of 27 CCRCCs and 9 normal kidney tissues as well as 15 various adult normal tissues were examined by Affymetrix U133 Plus 2.0 arrays. Among the 34 genes specifically up-regulated in CCRCC, overexpression of Toll-like receptor 3 (TLR3) mRNA and its protein was validated by quantitative reverse transcription-PCR, immunoblot, and immunohistochemistry...
October 1, 2007: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Ziad Thotathil, Michael B Jameson
Immunotherapy involves the treatment of cancer by modification of the host-tumour relationship. It is now known that this relationship is quite complex and only some of the interactions have been elucidated. Early attempts at immunotherapy, such as Coley's toxins, were undertaken without an understanding of the processes mediating the effects. With a better understanding of the immunology of this anticancer response, recent trials have focussed on certain aspects of the process to stimulate an antitumour response...
September 2007: Expert Opinion on Investigational Drugs
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