Department of Pharmaceutics, Institute of Pharmacy , University of Bonn , D-53121 Bonn , Germany.
PEPITE EA4267 , Univ. Bourgonge Franch-Comte , 25030 Besançon , France.
Mol Pharm. 2018 Nov 5;15(11):4777-4800. doi: 10.1021/acs.molpharmaceut.8b00691. Epub 2018 Oct 3.
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.
Toll-like Receptor 4 (TLR4) 激动剂在癌症免疫治疗领域已经走过了漫长的道路。尽管已经有大量的 TLR4 配体经历了各种临床前和临床阶段，但迄今为止只有两种（卡介苗（BCG）和单磷酰脂质 A（MPLA））获得了 FDA 批准用于癌症治疗的临床应用。本文全面回顾了 TLR4 激动剂作为癌症主动免疫治疗的历程。在简要讨论了 TLR 配体在癌症免疫治疗中的应用原理之后，我们将首先关注 TLR4 激动剂的先驱——细菌脂多糖（LPS）。在这方面，将讨论该药物免疫治疗的潜力和缺点，讨论为提高相关治疗效果而设计的策略，并总结随之而来的成就和缺点。随后，将介绍其他具有癌症免疫治疗潜力的分子、细菌和病毒 TLR4 激动剂，如果有的话，将回顾这些药物的临床前和临床研究结果。最后，我们将展望纳米技术这一相对较新领域的有前途的成果，提出 TLR4 激活纳米颗粒系统作为该领域未来发展的潜在候选物。
