Development of TLR9 agonists for cancer therapy
Arthur M. Krieg
Arthur M. Krieg
Published May 1, 2007
Citation Information: J Clin Invest. 2007;117(5):1184-1194. https://doi.org/10.1172/JCI31414.
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Review Series

Development of TLR9 agonists for cancer therapy

Abstract

In vertebrates, the TLRs are a family of specialized immune receptors that induce protective immune responses when they detect highly conserved pathogen-expressed molecules. Synthetic agonists for several TLRs, including TLR3, TLR4, TLR7, TLR8, and TLR9, have been or are being developed for the treatment of cancer. TLR9 detects the unmethylated CpG dinucleotides prevalent in bacterial and viral DNA but not in vertebrate genomes. As discussed in this Review, short synthetic oligodeoxynucleotides containing these immune stimulatory CpG motifs activate TLR9 in vitro and in vivo, inducing innate and adaptive immunity, and are currently being tested in multiple phase II and phase III human clinical trials as adjuvants to cancer vaccines and in combination with conventional chemotherapy and other therapies.

Authors

Arthur M. Krieg

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Figure 3

Potential mechanism to explain the observed antitumor synergy of TLR9 with chemotherapy.

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Potential mechanism to explain the observed antitumor synergy of TLR9 wi...
Tumor antigens are constitutively present in cancer patients and are taken up by DCs in the tumor and secondary lymphoid organs. In patients with established tumors, the immune system fails to respond to the tumor antigens due to the tumor-induced Tregs and other immune-suppressive effects. Certain chemotherapy regimens effectively deplete Tregs and also disrupt the tumor, releasing additional antigen and interfering with the ability of the tumor and its mesenchymal support structures to suppress the immune system. When such chemotherapy is followed by treatment with a TLR9 agonist (CpG ODN), DCs bearing tumor antigens are stimulated to mature and become effective inducers of a CTL response, which in the postchemotherapy environment is now better able to attack the tumor, leading to improved survival.