Development of CpG oligodeoxynucleotide TLR9 agonists in anti-cancer therapy. Issue 8 (3rd August 2021)

• Record Type: Journal Article
• Authors: Jin, Yizhen; Zhuang, Yuxin; Dong, Xiaowu; Liu, Mei
• Is Part Of: Expert review of anticancer therapy. Volume 21:Issue 8(2021)
• Page Start: 841
• Page End: 851
• Publication Date: 2021-08-03
• Subjects: Toll-like receptor-9 -- cpg odn -- cancer immunotherapy -- clinical trials -- optimization strategies; Cancer -- Treatment -- Periodicals; 616.99406
• DOI: 10.1080/14737140.2021.1915136
• Languages: English
• ISSNs: 1473-7140

Abstract

ABSTRACT: Introduction: Toll-like receptor-9(TLR9) can recognize the foreign unmethylated CpG DNA, and thus intrigue a strong Th1 response which plays a crucial role in the innate and adaptive immune responses. To date, CpG oligodeoxynucleotide (ODN)-based TLR9 agonists have undergone four generations. Each generations' breakthroughs in immune activation, safety profiles and pharmacokinetic properties were confirmed by both preclinical and clinical studies. Areas covered: We reviewed the development and major clinical trials of TLR9 agonists and summarized the optimization strategies of each generation. The applications, limitations and prospects of TLR9 agonists in cancer immunotherapy are also discussed. Expert opinion: Clinical trials of CpG ODN TLR9 agonists as a single agent demonstrated insufficient efficacy to reverse the immunosuppressive status of majority of patients with high tumor burden. Therefore, more efforts are now been carried out in combination with chemotherapy, radiotherapy and immunotherapy maintenance therapy as well as vaccine adjuvant. Importantly, the synergistic and complementary effect of TLR9 agonists and tumor immune checkpoint inhibitor therapy is expected to exert greater potential. On the other hand, the double-edged sword effect of TLR9 activation in tumor and toxic effect reported in combination therapies should be noted and further studies required.