426. dSLIM Immunomodulators Induce Anti- Tumor Responses Both In Vitro and In Vivo

Schmidt, Manuel; Cristóbal, Javier de; Sander, Astrid; Brzezicha, Bernadette; Merediz, Sven A. König; Wittig, Burghardt

doi:10.1016/j.ymthe.2006.08.491

Cited by 2 publications

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“…In an SKH1 murine model in which de novo papilloma development was initiated and promoted by topical application of chemicals (7,12-dimethylbenzanthracene and 12-Otetradecanoylphorbol-13-acetat), MGN1703 significantly reduced the number of mice developing papillomas compared with the saline control group, and the total number of papillomas on all mice was reduced by approximately 50% by MGN1703 [76]. Furthermore, several syngeneic murine tumor models were established: a melanoma model with subcutaneous or i.v.…”

Section: Preclinical Antitumor Activity Of Mgn1703mentioning

confidence: 98%

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: Preclinical Antitumor Activity Of Mgn1703mentioning

confidence: 98%

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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Maintenance treatment with the immunomodulator MGN1703, a Toll-like receptor 9 (TLR9) agonist, in patients with metastatic colorectal carcinoma and disease control after chemotherapy: a randomised, double-blind, placebo-controlled trial

Schmoll

Wittig²,

Arnold³

et al. 2014

J Cancer Res Clin Oncol

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PurposeThis phase II study evaluated the synthetic DNA-based immunomodulator and Toll-like receptor 9 agonist MGN1703 as maintenance treatment in metastatic colorectal carcinoma (mCRC).MethodsFifty-nine patients with mCRC and disease control after standard first-line chemotherapy were randomised to MGN1703 60 mg (N = 43) or placebo (N = 16).ResultsThe hazard ratio (HR) for the primary endpoint [progression-free survival (PFS) from the start of maintenance] was 0.56 (95 % CI 0.29–1.08; P = 0.07) and 0.55 (95 % CI 0.3–1.0; P = 0.04) by independent and investigator review, respectively. MGN1703 significantly improved PFS measured from the start of induction therapy versus placebo on independent (HR 0.49; 95 % CI 0.26–0.94; P = 0.03) and investigator review (HR 0.50; 95 % CI 0.31–1.02; P = 0.02). Overall survival (OS) data remain immature (HR 95 %; 95 % CI 0.3–1.5; P = 0.29) with 28/43 patients alive after a medium follow-up of >17 months. Retrospective subgroup analysis showed a significant effect of MGN1703 on PFS versus placebo in patients with greater than median tumour size reduction and normalised carcinoembryonic antigen concentrations following induction therapy, and in patients with elevated activated NKT cells ≥3.08 %. Adverse events were mild to moderate and limited to injection-site reactions or linked to general immune system activation.ConclusionsMGN1703 maintenance treatment was well tolerated and appears to induce durable and prolonged PFS and disease control in a subgroup of patients with mCRC following induction therapy. Activated NKT cells may be a predictive biomarker for selecting patients likely to benefit more from MGN1703.Electronic supplementary materialThe online version of this article (doi:10.1007/s00432-014-1682-7) contains supplementary material, which is available to authorized users.

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426. dSLIM Immunomodulators Induce Anti- Tumor Responses Both In Vitro and In Vivo

Cited by 2 publications

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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

Maintenance treatment with the immunomodulator MGN1703, a Toll-like receptor 9 (TLR9) agonist, in patients with metastatic colorectal carcinoma and disease control after chemotherapy: a randomised, double-blind, placebo-controlled trial

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