Development of CpG oligodeoxynucleotide TLR9 agonists in anti-cancer therapy

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.

KEYWORDS:

• Toll-like receptor-9
• cpg odn
• cancer immunotherapy
• clinical trials
• optimization strategies

Article highlights

• TLR9 agonists showed promising efficacy in different anti-cancer therapies.

• Optimization strategies of each generation of TLR9 agonists are discussed.

• The results of important clinical trials are reviewed.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work was supported by grant from the Zhejiang Provincial Natural Science Foundation (LQ19H090013).