A phase III randomized study of gemcitabine and cisplatin with or without PF-3512676 (TLR9 agonist) as first-line treatment of advanced non-small-cell lung cancer

Manegold, Christian; Zandwijk, Nico van; Szczęsna, A.; Zatloukal, Petr; Au, Joseph Siu-Kie; Błasińska-Morawiec, Maria; Serwatowski, Piotr; Krzakowski, Maciej; Jassem, Jacek; Tan, Eng Huat; Benner, Rebecca J.; Ingrosso, Antonella; Meech, Sandra J.; Readett, David; Thatcher, Nick

doi:10.1093/annonc/mdr030

Cited by 116 publications

(79 citation statements)

References 17 publications

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“…75 Moreover, in the Phase III clinical trial in which a CpG-B ODN (PF-3512676, also known as ODN2006 or CpG-7909) was combined with standard chemotherapy, it was reported that patients administered with the CpG-B ODN had a high probability of developing adverse events. 114,115 The results of these preclinical and clinical studies suggest that CpG ODNs with a phosphodiester backbone would be preferable to those with a phosphorothioate backbone. CpG ODNs with a phosphodiester backbone can provide DNase resistance in the self-assembled CpG ODNs, protein/peptide-CpG ODN conjugates, and nanomaterial-CpG ODN complexes.…”

Section: Prospects For the Futurementioning

confidence: 99%

CpG oligodeoxynucleotide nanomedicines for the prophylaxis or treatment of cancers, infectious diseases, and allergies

Hanagata

2017

IJN

110

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Section: Prospects For the Futurementioning

confidence: 99%

CpG oligodeoxynucleotide nanomedicines for the prophylaxis or treatment of cancers, infectious diseases, and allergies

Hanagata

2017

IJN

110

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“…This unexpected finding led us to further investigate the potential impact of TLR9 activation on immune cells from HIV-infected individuals. However, the significant toxicity associated with treatment with such a CpG-ODN is a significant barrier to clinical development (10,12,13). The phosphorothioate backbone that prevents nuclease-mediated degradation of CpG-ODN molecules has off-target immunostimulatory effects, which may increase and/or worsen adverse events (14).…”

mentioning

confidence: 99%

A Novel Toll-Like Receptor 9 Agonist, MGN1703, Enhances HIV-1 Transcription and NK Cell-Mediated Inhibition of HIV-1-Infected Autologous CD4 ⁺ T Cells

Offersen

Nissen

Rasmussen

et al. 2016

J Virol

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Toll-like receptor (TLR) agonists are potent enhancers of innate antiviral immunity and may also reverse HIV-1 latency. Therefore, TLR agonists have a potential role in the context of a "shock-and-kill" approach to eradicate HIV-1. Our extensive preclinical evaluation suggests that a novel TLR9 agonist, MGN1703, may indeed perform both functions in an HIV-1 eradication trial. Over the past decade, the importance of NK cells in controlling human immunodeficiency virus type 1 (HIV-1) infection in vivo has become increasingly clearer (1-3). In response, novel approaches to induce NK cell-directed enhancement of immune function are being developed (4). One approach to improving NK cell function is via Toll-like receptor 9 (TLR9) activation.TLR9 ligands stimulate potent antiviral responses via an activation pathway initiated by the TLR9 recognition of nonmethylated cytosine-guanine dinucleotide (CG) motifs found in bacterial, viral, and mitochondrial DNAs (5). This pathway is initiated by pattern recognition in plasmacytoid dendritic cells (pDCs) and B cells, as these cells exhibit high levels of TLR9 expression. Following TLR9 engagement, type I interferon (primarily interferon alpha [IFN-␣]) is produced and secreted by pDCs. IFN-␣ activates NK cells as well as the promoters of interferon-stimulated genes (e.g., CXCL-10), resulting in a targeted antiviral inflammatory environment. T and NK cells within this local environment become further activated (e.g., upregulated CD69 surface expression on NK and T cells and altered expression of NK cell receptors) (6). The overall function of activated T and NK cells is to clear the pathogen that initiated the cascade in the TLR9-expressing cells.

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“…Moreover, our results suggest that TLR9 expression is a prognosis biomarker in TNCs, and highlight the interest of initiating clinical trials combining TLR9 agonists and STAT3 inhibitors in TNCs. These results also warrant studies of other altered genes identified in the present study as putative predictive biomarkers for selecting patients most likely to benefit from these drugs [56].…”

Section: Discussionmentioning

confidence: 54%

Biopathological Significance of TLR9 Expression in Cancer Cells and Tumor Microenvironment Across Invasive Breast Carcinomas Subtypes

Meseure

Vacher

Alsibai

et al. 2016

Cancer Microenvironment

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Toll-like receptors (TLRs) are pattern recognition receptors mainly expressed by cells of the immune system but also by epithelial tumor cells. Little is known about expression patterns of TLR genes in breast tumors, and their clinical significance is unclear. The aim of our study was to investigate expression of TLRs pathway components in pre-invasive breast lesions and invasive breast carcinomas (IBCs). We used RT-PCR assays to quantify mRNA levels of the 10 TLR genes and genes involved in TLR pathways in 350 breast tumors from patients with known clinical/pathological status and long-term outcome. Sets of 158 breast samples were also analyzed by immunochemistry including; 40 early noninvasive breast lesions, 38 IBCs and 80 triple negative carcinomas subtype (TNCs). We identified TLR9 as the major TLR gene family member upregulated in breast tumors and more particularly in TNCs. Immunohistochemical studies demonstrated that TLR9 protein was expressed in tumor epithelial and stromal cells of the TLR9 mRNA-overexpressing tumors. TLR9 overexpression appears very early during breast carcinogenesis. High TLR9 levels were associated with favorable outcome in the TNC sub-group. TLR9 overexpression was associated with alterations of down-stream components of the TLR9 signaling pathway, epithelio-mesenchymal transition (EMT) induction and EGFR pathway deregulation. TNCs with TLR9 overexpression were significantly correlated with development of a fibrous and inflammatory microenvironment with variable status of nuclear phosphoSTAT3. Our results suggest that TLR9 could play a role in TNC carcinogenesis and could be useful as predictive biomarker and therapeutic target.Keywords Toll-like receptor 9 . Breast cancer subtypes .

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A phase III randomized study of gemcitabine and cisplatin with or without PF-3512676 (TLR9 agonist) as first-line treatment of advanced non-small-cell lung cancer

Cited by 116 publications

References 17 publications

CpG oligodeoxynucleotide nanomedicines for the prophylaxis or treatment of cancers, infectious diseases, and allergies

CpG oligodeoxynucleotide nanomedicines for the prophylaxis or treatment of cancers, infectious diseases, and allergies

A Novel Toll-Like Receptor 9 Agonist, MGN1703, Enhances HIV-1 Transcription and NK Cell-Mediated Inhibition of HIV-1-Infected Autologous CD4 ⁺ T Cells

Biopathological Significance of TLR9 Expression in Cancer Cells and Tumor Microenvironment Across Invasive Breast Carcinomas Subtypes

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A phase III randomized study of gemcitabine and cisplatin with or without PF-3512676 (TLR9 agonist) as first-line treatment of advanced non-small-cell lung cancer

Cited by 116 publications

References 17 publications

CpG oligodeoxynucleotide nanomedicines for the prophylaxis or treatment of cancers, infectious diseases, and allergies

CpG oligodeoxynucleotide nanomedicines for the prophylaxis or treatment of cancers, infectious diseases, and allergies

A Novel Toll-Like Receptor 9 Agonist, MGN1703, Enhances HIV-1 Transcription and NK Cell-Mediated Inhibition of HIV-1-Infected Autologous CD4 + T Cells

Biopathological Significance of TLR9 Expression in Cancer Cells and Tumor Microenvironment Across Invasive Breast Carcinomas Subtypes

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A Novel Toll-Like Receptor 9 Agonist, MGN1703, Enhances HIV-1 Transcription and NK Cell-Mediated Inhibition of HIV-1-Infected Autologous CD4 ⁺ T Cells