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

Highlights

• TLR-9 agonists activate innate and adaptive immunity against cancer.

• Chemically stabilized CpG-ODN type showed insufficient clinical efficacy.

• Structure-stabilized MGN1703 is well tolerated at repeated applications of high doses.

• Immune activation profile of MGN1703 holds therapeutic potential in variety of tumors.

• First-line switch maintenance trial in metastatic colorectal cancer is underway.

Abstract

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.