Phase I clinical study of the toll-like receptor 9 agonist MGN1703 in patients with metastatic solid tumours

Weihrauch, Martin R.; Richly, Heike; Bergwelt‐Baildon, Michael S. von; Becker, H.; Schmidt, Manuel; Hacker, Ulrich; Shimabukuro‐Vornhagen, Alexander; Holtick, Udo; Nokay, B.; Schroff, Matthias; Wittig, Burghardt; Scheulen, M. E.

doi:10.1016/j.ejca.2014.11.002

Cited by 60 publications

(48 citation statements)

References 26 publications

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“…Of these, three patients demonstrated prolonged SD with non-small-cell lung cancer (18 months), melanoma (15 months) and CRC (6 months). A fourth patient with CRC achieved almost PR (29.7% of tumor reduction) during this time and continued treatment for 17 months until disease progression [81]. Immunological assessments in this study revealed that treatment with MGN1703 was associated with an increase in the relative number of TLR-9-expressing naïve B cells and a reduction in memory B cells.…”

Section: Phase I Study In Metastatic Solid Tumors: Mgn1703 As a Theramentioning

confidence: 63%

“…A subsequent open-label phase I dose-finding study has also been completed that evaluated the safety and toxicity of higher doses of MGN1703 in 28 patients with metastatic solid tumors who had failed standard therapy [81][82][83]. The study had two parts; a single-dose phase (15 patients) and a multiple-dose phase (24 patients, 11 of which were included from the single-dose phase), with MGN1703 administered subcutaneously at dose levels of 0.25-60 mg in each phase.…”

Section: Phase I Study In Metastatic Solid Tumors: Mgn1703 As a Theramentioning

confidence: 99%

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MGN1703, an immunomodulator and toll-like receptor 9 (TLR-9) agonist: From bench to bedside

Wittig¹,

Schmidt

Scheithauer³

et al. 2015

Critical Reviews in Oncology/Hematology

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The adaptive immune system has been the main focus of immunological strategies in oncology with only more recent approaches targeting innate immunity. Endosomal toll-like receptors (TLR-7, TLR-9) activate innate immune responses by signaling damage-associated molecular patterns (DAMP) from decaying tumor cells. This has led to the development of DNA-based TLR-9 agonists, which induce antitumor activity through innate and subsequent adaptive immune responses. Early clinical trials with CpG-ODN as TLR-9 agonists were associated with unfavorable tolerability and narrow clinical efficacy, leading to failure in pivotal trials. dSLIM, the active ingredient of MGN1703, is a DNA-based, radically different molecular alternative to CpG-ODN, which results in genuine antitumor immunomodulation. Preclinical and clinical studies of MGN1703 have confirmed that this TLR-9 agonist has therapeutic potential in a variety of solid tumors, while long-term treatment with high doses was very well tolerated. A pivotal trial of first-line maintenance treatment with MGN1703 in patients with metastatic colorectal cancer is underway.

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Section: Phase I Study In Metastatic Solid Tumors: Mgn1703 As a Theramentioning

confidence: 63%

Section: Phase I Study In Metastatic Solid Tumors: Mgn1703 As a Theramentioning

confidence: 99%

MGN1703, an immunomodulator and toll-like receptor 9 (TLR-9) agonist: From bench to bedside

Wittig¹,

Schmidt

Scheithauer³

et al. 2015

Critical Reviews in Oncology/Hematology

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“…In the MGN1703 Phase I clinical trial targeting patients with metastatic solid tumors, the antitumor efficacy and safety of the self-assembled CpG nanomedicine was confirmed, and the dosage was also determined (60 mg twice a week). 76 The Phase II clinical trial assessed MGN1703 maintenance treatment for metastatic colorectal carcinoma, and the results showed significantly improved progression-free survival. 77 MGN1703 also increased the IgG2 levels induced by Th1-biased responses in PBMCs.…”

Section: Cpg Odn Nanomedicinesmentioning

confidence: 99%

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

Hanagata

2017

IJN

110

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“…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). Because MGN1703's unique structure, comprising only natural DNA, obviates the need for such chemical modifications, MGN1703 has an excellent safety profile, which has been demonstrated during clinical testing (15,16).…”

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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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Phase I clinical study of the toll-like receptor 9 agonist MGN1703 in patients with metastatic solid tumours

Cited by 60 publications

References 26 publications

MGN1703, an immunomodulator and toll-like receptor 9 (TLR-9) agonist: From bench to bedside

MGN1703, an immunomodulator and toll-like receptor 9 (TLR-9) agonist: From bench to bedside

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

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Phase I clinical study of the toll-like receptor 9 agonist MGN1703 in patients with metastatic solid tumours

Cited by 60 publications

References 26 publications

MGN1703, an immunomodulator and toll-like receptor 9 (TLR-9) agonist: From bench to bedside

MGN1703, an immunomodulator and toll-like receptor 9 (TLR-9) agonist: From bench to bedside

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

Contact Info

Product

Resources

About

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