Applications and clinical trial landscape using Toll-like receptor agonists to reduce the toll of cancer

Abstract

Toll-like receptors (TLRs), which serve as a bridge between innate and adaptive immunity, may be viable treatment targets. TLRs are the first line of defense against microbes and activate signaling cascades that induce immune and inflammatory responses. Patients with “hot” versus “cold” tumors may respond more favorably to immune checkpoint inhibition, and through their downstream effects, TLR agonists have the potential to convert “cold tumors” into “hot tumors” making TLRs in combination with immune checkpoint inhibitors, potential targets for cancer therapies. Imiquimod is a topical TLR7 agonist, approved by the FDA for antiviral and skin cancer treatments. Other TLR adjuvants are used in several vaccines including Nu Thrax, Heplisav, T-VEC, and Cervarix. Many TLR agonists are currently in development as both monotherapy and in combination with immune checkpoint inhibitors. In this review, we describe the TLR agonists that are being evaluated clinically as new therapies for solid tumors.

Keratin 6a attenuates Toll-like receptor-triggered proinflammatory response in corneal epithelial cells by suppressing ELKS/IKKε-dependent activation of NF-κB

“…If not treated properly the sequelae of these inflammatory conditions can inflict collateral damage to the remaining healthy cornea tissues compromising their barrier and refractive functions, leading to extensive scarring and even vision loss. Interestingly, while TLR2/4 agonist MPLA and TLR7 agonist imiquimod are approved by the Food and Drug Administration as a vaccine adjuvant and for treating viral infection and skin cancer respectively (Wang et al 2020; Rolfo et al 2023), no TLR antagonists have been approved for clinical use perhaps due to systemic toxicities. As such, the development of TLR inhibitors that are cell or tissue type specific and with improved tolerability can have beneficial therapeutic potentials for unmet medical needs.…”

Proton-Gradient-Driven Porphyrin-Based Liposome Remote-Loaded with Imiquimod as In Situ Nanoadjuvants for Synergistically Augmented Tumor Photoimmunotherapy

“…Adjuvants can effectively improve the efficiency of antigen presentation and thus play a crucial role in tumor immunotherapy. , At present, only aluminum adjuvant has been approved by the FDA for clinical application . Aluminum adjuvant can only activate humoral immunity but cannot activate cellular immunity, and the dosage form of aluminum adjuvant is limited to suspension, emulsion, etc., which limits clinical application. , Toll-like receptor (TLR) agonists can activate a family of transmembrane receptors that are expressed on immune and nonimmune cells, such as TLR2 agonist lysophosphatidic acid, TLR3 agonist [polyinosinic acid-polycytidylic acid (poly-IC)], TLR4 agonist [lipopolysaccharide (LPS)], TLR5 agonist [recombinant flagellin (CBLB502)], TLR7/8 agonist (imiquimod, R837), and TLR9 agonist [family CpG oligodeoxynucleotides (CpG ODN)], − and activated TLRs are able to recognize pathogen-associated molecular pattern molecules and damage-associated molecular pattern molecules. Compared to these mentioned TLR agonists, the TLR7 agonist R837 has the following unique features: (1) high specificity; (2) a well-tolerated safety profile approved by the FDA; and (3) specifically activate cellular and humoral immunity. , Nevertheless, TLR agonists (e.g., imiquimod, R837) are highly hydrophobic, and the target of TLR agonists is on the inner membrane of endosomes or lysosomes; then, systemic administration of small-molecule drugs tends to induce hyperimmunity or off-target effects, such as headache, and even cytokine storms. − Fortunately, nanodrug delivery systems can not only improve the solubility of poorly soluble drugs but, more importantly, also endow them with controlled release and targeted distribution in vivo .…”

Design, synthesis and biological evaluation of quinazoline and pyrrolo[3,2-d]pyrimidine derivatives as TLR7 agonists for antiviral agents

“…TLR7 agonists have promising applications in the treatment and prevention of tumours. Various TLR7 agonists have been studied for the treatment of viral skin lesions and skin cancer, [24][25][26] and R837 has been shown to suppress hepatocellular carcinoma. 8 The antitumor effects of TLR7 agonists have been extensively researched.…”