According to the World Health Organization, cancer is a leading cause of death worldwide and lung cancer is one of the five most common cancers in both men and women. Despite advances made in treatment, unless diagnosed at an early clinical stage, the majority of lung cancer patients in the United States die within five years of diagnosis.
Polynucleotides containing unmethylated CG dinucleotides stimulate the innate immune system by activating cells expressing Toll-like receptor 9 (TLR9). Several polynucleotide TLR9 agonists have been tested as immunotherapeutic agents for cancer. While results of preclinical and phase II trials of a polynucleotide TLR9 agonist were promising, the polynucleotide TLR9 agonist did not improve survival of patients with non-small cell lung cancer when added to a chemotherapy regimen (Schmidt, Nature Biotechnology, 25:825-826, 2007). More recently, the route of administration of polynucleotide TLR9 agonists has been shown to be critical, with intratumoral injection resulting in superior antitumor immune responses than intravenous injection (Lou et al., J Immunother, 34:279-288, 2011).
Direct intratumoral injection of primary and metastatic tumors in the lung is generally not feasible. However, intrapulmonary delivery of polynucleotide TLR9 agonists has been shown to result in potent anti-tumor responses in mouse models of lung metastases (Sato et al., Mol Cancer Ther, 14:2198-2205, 2015; and Sfondrini et al., Inter J Cancer, 133:383-394, 2013). Even so, polynucleotide TLR9 agonists must have an appropriate therapeutic window for intrapulmonary administration to human cancer patients.
Thus, what the art needs are polynucleotide TLR9 agonists with high potency and low toxicity.