Toll-Like Receptor 9 Agonists for Cancer Therapy

Abstract

The immune system has acquired increasing importance as a key player in cancer maintenance and growth. Thus, modulating anti-tumor immune mediators has become an attractive strategy for cancer treatment. Toll-like receptors (TLRs) have gradually emerged as potential targets of newer immunotherapies. TLR-9 is preferentially expressed on endosome membranes of B-cells and plasmacytoid dendritic cells (pDC) and is known for its ability to stimulate specific immune reactions through the activation of inflammation-like innate responses. Several synthetic CpG oligonucleotides (ODNs) have been developed as TLR-9 agonists with the aim of enhancing cancer immune surveillance. In many preclinical models, CpG ODNs were found to suppress tumor growth and proliferation both in monotherapy and in addition to chemotherapies or target therapies. TLR-9 agonists have been also tested in several clinical trials in patients with solid tumors. These agents showed good tolerability and usually met activity endpoints in early phase trials. However, they have not yet been demonstrated to significantly impact survival, neither as single agent treatments, nor in combination with chemotherapies or cancer vaccines. Further investigations in larger prospective studies are required.

Keywords: CpG ODN; PF-3512676; TLR-9; immune modulatory oligonucleotides.

Figure 1

CpG-DNA–TLR-9 cell signaling. CpG oligodeoxynucleotides (ODNs) enter into endosomal vesicles that contain toll-like receptor 9 (TLR-9) through clathrin-coated vesicles. The interaction between CpG-DNA and TLR-9 initiates an intracellular activation signal. The signal starts with the recruitment of myeloid differentiation primary response gene 88 (MyD88) to the toll-interleukin-1 receptor (TIR) domain of TLR-9, followed by activation of the IRAK1–TRAF6 complex. Later, TRAF6 recruits TAK1, TAB-2, TAB-3, UBC-13 and UEV-1A. This complex leads to the activation of both the mitogen-activated protein kinase (MAPK: AP-1) and the nuclear factor-κB (NF-κB) kinase inhibitor (IKK), culminating in the up-regulation of transcription factors, including NF-κB and activating protein 1 (AP1). IRAK, IL-1 receptor-activated kinase; TRAF, tumor necrosis factor (TNF)-receptor-associated factor; TAB, TAK1 binding proteins; IκB, inhibitor of kappa B.