Early development of the Toll-like receptor 9 agonist, PF-3512676, for the treatment of patients with advanced cancers

Unmethylated oligodeoxynucleotides (ODNs) with cytosine-phosphate-guanine (CpG) motifs can potently activate the immune system through Toll-like receptor (TLR) 9. PF-3512676 is a synthetic CpG ODN that induces strong Th1-type immune responses through TLR9 and is now in clinical development.To review discovery and development of synthetic CpG ODNs and their effects on immune cells and to relate preclinical and early clinical development of PF-3512676.A literature search was performed on databases available through the National Library of Medicine (PubMed), the European Society of Medical Oncology and the American Society of Clinical Oncology.Unmethylated CpG motifs were identified as the element of bacillus Calmette-Guérin responsible for immunostimulatory activity. Preclinical studies identified the mechanism of action (i.e., TLR9) and an optimal human sequence for antitumor activity. On the basis of preclinical studies, PF-3512676, a B-class CpG ODN, was selected for further clinical development. Phase I/II clinical trials have shown PF-3512676 to be well tolerated and to have antitumor activity as a single agent in patients with several types of advanced cancer, and to show promise as a vaccine adjuvant.