Toll-like receptor 9 agonists as cancer therapeutics.
BACKGROUND
Toll-like receptor 9 (TLR9) agonists, commonly referred to as CpG oligodeoxynucleotides (ODN), have been added to the arsenal of anti-cancer drugs as monotherapy or in combination with chemotherapy, radiotherapy and other immunotherapeutic approaches as they increase antigen presentation and boost anti-tumor T- and B-cell responses. Several synthetic TLR9 agonists have been developed for clinical grade use and displayed substantial efficacy in the preclinical and clinical models.


METHODS
This review summarizes TLR9 signaling and the impact of TLR9 agonists on the immune response. The most recent experimental and clinical data are analyzed as well as the development of new TLR9 agonists in current clinical trials.


CONCLUSIONS
Application of TLR9 agonists, in particular, combination strategies with chemo- or radiotherapy seem a promising and efficient immunotherapeutic approach in cancer patients even with refractory disease. Simultaneous application of TLR9 agonists aims at supporting the patient's immune response and overcoming specific immunosuppressant strategies developed by tumors. Combinatory approaches of the future might also seek for synergism of TLR9 agonists with other immunomodulatory strategies such as B-cell activation using the CD40-CD40L system.
University of Cologne, Department I for Internal Medicine, Hematology, Oncology, Cologne, Germany. udo.holtick@uk-koeln.de
Udo
U
Holtick
Max E
ME
Scheulen
Michael S
MS
von Bergwelt-Baildon
Martin R
MR
Weihrauch
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D002986:Clinical Trials as Topic; D018899:CpG Islands; D006801:Humans; D007155:Immunologic Factors / Q000627:therapeutic use; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D009841:Oligonucleotides / Q000276:immunology / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology; D051217:Toll-Like Receptor 9 / Q000819:agonists* / Q000276:immunology / Q000378:metabolism
D000970:Antineoplastic Agents; D007155:Immunologic Factors; D009841:Oligonucleotides; D051217:Toll-Like Receptor 9