TLR4-Based Immunotherapeutics in Cancer: A Review of the Achievements and Shortcomings

Abstract

Toll-like Receptor 4 (TLR4) agonists have had a long journey in the field of cancer immunotherapy. Nevertheless, despite the remarkable number of the TLR4 ligands that have gone through various preclinical and clinical stages, only two (Bacillus Calmette-Guérin (BCG) and monophosphoryl lipid A (MPLA)) have hitherto obtained the FDA approval for clinical application in cancer treatment. This paper provides a comprehensive review of the TLR4 agonists' journey as cancer active immunotherapeutics. Following a brief discussion of the rationale behind the use of TLR ligands in cancer immunotherapy, we will initially focus on the forerunner of the TLR4 agonists, bacterial lipopolysaccharide (LPS). Within this context, the potentials and shortcomings of immunotherapy with this agent will be addressed, the strategies that have been devised to enhance the associated therapeutic outcome will be discussed, and the consequent achievements and shortcomings will be summarized. Subsequently, further and perhaps less well-known, molecular, bacterial, and viral TLR4 agonists with potential for cancer immunotherapy will be introduced, and if present, the outcome of the preclinical and clinical investigations of these agents will be reviewed. Finally, a look will be cast upon the promising souvenirs of the relatively new arena of nanotechnology, where TLR4 activating nanoparticulate systems will be proposed as potential candidates for the future development of this field.

Adjuvant-pulsed mRNA vaccine nanoparticle for immunoprophylactic and therapeutic tumor suppression in mice

“…Adjuvants can improve immune responses by activating APCs to increase antigen presentation (signal 1), promote the co-expression of costimulatory molecules (signal 2) and the production of specific cytokines (signal 3) that, when properly coordinated, enhance T cell responses [ 68 ]. Adjuvants currently approved for human use in Europe and the United States include aluminum salts, oil-in-water emulsions as well as TLR4 and TLR9 adjuvants [ 69 ]. Aluminum salts and oil-in-water emulsions are the most commonly used, however they are limited by their need for repeated administration in order to induce protection [ 55 ].…”

Cationic Nanostructures for Vaccines Design

“…Dendritic cells (DC) process and present antigens to T lymphocytes, inducing potent immune responses when encountered in association with activating signals, such as pathogen-associated molecular patterns. Monophosphoryl lipid A (MPL) is a ligand of the Toll-like receptor-4 and has been used in several studies on vaccines [ 100 ]. Using combined therapy against murine model tumors, both MPL and IL-12 were included in cationic DOTAP liposomes for intratumoral injection [ 101 ].…”

Nanomedicine-mediated alteration of the pharmacokinetic profile of small molecule cancer immunotherapeutics

“…Nanoparticles are mainly presented here as a means to improve the delivery to immune cells and decrease systemic exposure of adjuvants. However, multiple examples exist of nanostructures being immune-stimulating on themselves, of which some of these work by triggering of TLR4 [ 77 , 78 ]. An example of these nanostructures with TLR4 agonist properties is the self-assembling peptide developed by Tandon et al [ 79 ].…”