Trial Watch: experimental TLR7/TLR8 agonists for oncological indications

Abstract

Resiquimod (R848) and motolimod (VTX-2337) are second-generation experimental derivatives of imiquimod, an imidazoquinoline with immunostimulatory properties originally approved by the US Food and Drug Administration for the topical treatment of actinic keratosis and genital warts more than 20 years ago. Both resiquimod and motolimod operate as agonists of Toll-like receptor 7 (TLR7) and/or TLR8, in thus far delivering adjuvant-like signals to antigen-presenting cells (APCs). In line with such an activity, these compounds are currently investigated as immunostimulatory agents for the treatment of various malignancies, especially in combination with peptide-based, dendritic cell-based, cancer cell lysate-based, or DNA-based vaccines. Here, we summarize preclinical and clinical evidence recently collected to support the development of resiquimod and motolimod and other TLR7/TLR8 agonists as anticancer agents.

Oxyresveratrol Inhibits R848-Induced Pro-Inflammatory Mediators Release by Human Dendritic Cells Even When Embedded in PLGA Nanoparticles

“…The interaction between DCs and pathogenic microorganisms triggers the secretion of various cytokines that stimulate the inflammatory process and the immune response [ 22 ]. We then investigated whether free oxyresveratrol would be able to modulate the cytokine release elicited by DC challenge with R848, a molecule binding the toll like receptor (TLR)7 and TLR8, which are pattern recognition receptors (PRRs) sensing viral RNA and activating the immune cells [ 23 , 24 ]. For this purpose, blood monocyte-derived DCs were treated with 50 or 100 μM free oxyresveratrol, both in the absence or presence of 5 μM R848.…”

“…In this paper we report the results of investigations aimed at clarifying whether a mechanism by which oxyresveratrol inhibits the inflammation resides in a decreased secretion of pro-inflammatory cytokines by DCs. Here we show that oxyresveratrol suppressed the secretion of IL-12, TNF-α and IL-6 by human DCs stimulated with R848, an agonist of TLR 7 and TLR 8 which recognize single stranded RNA viruses such as Influenza, Sendai, Coxackie B, HIV and HCV [ 23 , 24 ]. Therefore, cell stimulation with R848 mimics the natural interaction between DCs and some pathogen viruses, and the results obtained suggest that oxyresveratrol could be a good tool to mitigate the inflammatory response elicited by these microorganisms.…”

Toll-Like Receptor 7 Mediates Inflammation Resolution and Inhibition of Angiogenesis in Non-Small Cell Lung Cancer

“…Due to their potent immuno-stimulatory activity on immune cells, ligands to TLR7 have been evaluated as immunotherapeutic agents with anticancer activity in several pre-clinical models [ 58 ]. A very recent study highlights the strong antitumor activity of resiquimod (TLR7 agonist, analogue to imiquimod) in NSCLC due to its effects of immuno-modulation of the tumor microenvironment.…”

Molecular Immunotherapy: Promising Approach to Treat Metastatic Colorectal Cancer by Targeting Resistant Cancer Cells or Cancer Stem Cells

“…Over many years, the potent stimulatory effects of Toll-like receptors (TLRs) on the immune system have urged efforts aiming to develop immune vaccines that use TLR agonists as immunological adjuvants (31,32). Motolimod (VTX-2337) and resiquimod (R848) are TLR-8 and TLR-7/TLR-8 agonists respectively, that deliver adjuvant-like signals to APCs.…”

“…VTX-2337 and R848 are currently being investigated as potential immune system stimulators for the treatment of various tumor types (including CRC and mCRC). They might be particularly considered effective in combination therapies together with cancer cell lysate-based, dendritic cell-based, DNA molecules-based or peptide-based vaccines (31). The CD200 receptor (CD200R) inhibits immune activation upon binding to its ligand CD200 that is often expressed on tumor cells to diminish anti-cancer immune response (33,34).…”