Ahmad A Tarhini1, John M Kirkwood, Arthur M Krieg. 1. Assistant Professor of Medicine University of Pittsburgh School of Medicine, University of Pittsburgh Cancer Institute, UPMC Cancer Pavilion, 5150 Centre Avenue, RM 555 Pittsburgh, Pennsylvania, USA +1 412 648 6507 ; +1 412 648 6579 ; tarhiniaa@upmc.edu.
Abstract
BACKGROUND: 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. OBJECTIVE: 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. METHODS: 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. RESULTS/ CONCLUSIONS: 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.
BACKGROUND: 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. OBJECTIVE: 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. METHODS: 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. RESULTS/ CONCLUSIONS: 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.
Authors: Ahmad A Tarhini; Siyang Leng; Stergios J Moschos; Yan Yin; Cindy Sander; Yan Lin; William E Gooding; John M Kirkwood Journal: J Immunother Date: 2012-05 Impact factor: 4.456
Authors: Kerstin Kapp; Barbara Volz; Michael A Curran; Detlef Oswald; Burghardt Wittig; Manuel Schmidt Journal: J Immunother Cancer Date: 2019-01-08 Impact factor: 13.751