Toll-Like Receptor 9 Agonists in Cancer

• Main Authors: Karapetyan L, Luke JJ, Davar D
• Format: Article
• Language: English
• Published: Dove Medical Press 2020-10-01
• Series: OncoTargets and Therapy
• Subjects: toll-like receptor; tlr; tlr9; cpg; odn; innate immunity; innate agonist; cancer; cancer immunotherapy; dendritic cell
• Online Access: https://www.dovepress.com/toll-like-receptor-9-agonists-in-cancer-peer-reviewed-article-OTT

Lilit Karapetyan,1 Jason J Luke1,2 *,* Diwakar Davar1,2 ** 1University of Pittsburgh Medical Center (UPMC) Hillman Cancer Center (HCC), Pittsburgh, PA, USA; 2Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA*These authors contributed equally to this workCorrespondence: Diwakar DavarUniversity of Pittsburgh Medical Center and Hillman Cancer Center, UPCI Research Pavilion, 5115 Centre Ave, Suite 1.32d, Pittsburgh, PA 15213, USATel [phone]Fax [phone]Email [e-mail] J LukeUniversity of Pittsburgh Medical Center and Hillman Cancer Center, 5115 Centre Ave, Pittsburgh, PA 15213, USATel [phone]Fax [phone]Email [e-mail]: Toll-like receptor 9 (TLR9) is a pattern recognition receptor that is predominantly located intracellularly in immune cells, including dendritic cells, macrophages, natural killer cells, and other antigen-presenting cells (APC). The primary ligands for TLR9 receptors are unmethylated cytidine phosphate guanosine (CpG) oligodinucleotides (ODN). TLR9 agonists induce inflammatory processes that result in the enhanced uptake and killing of microorganisms and cancer cells as well as the generation of adaptive immune responses. Preclinical studies of TLR9 agonists suggested efficacy both as monotherapy and in combination with several agents, which led to clinical trials in patients with advanced cancer. In these studies, intravenous, intratumoral, and subcutaneous routes of administration have been tested; with anti-tumor responses in both treated and untreated metastatic sites. TLR9 agonist monotherapy is safe, although efficacy is minimal in advanced cancer patients; conversely, combinations appear to be more promising. Several ongoing phase I and II clinical trials are evaluating TLR9 agonists in combination with a variety of agents including chemotherapy, radiotherapy, targeted therapy, and immunotherapy agents. In this review article, we describe the distribution, structure and signaling of TLR9; discuss the results of preclinical studies of TLR9 agonists; and review ongoing clinical trials of TLR9 agonists singly and in combination in patients with advanced solid tumors.Keywords: toll-like receptor, TLR, TLR9, CpG, ODN, innate immunity, innate agonist, cancer, cancer immunotherapy, dendritic cell