Combination therapy targeting toll like receptors 7, 8 and 9 eliminates large established tumors

BACKGROUND: The TLR7/8 agonist 3M-052 and the TLR9 agonist CpG ODN both trigger innate immune responses that support the induction of tumor-specific immunity. Previous studies showed that these agonists used individually could improve the survival of mice challenged with small tumors but were of limited therapeutic benefit against large/advanced tumors. METHODS: Normal mice were challenged with syngeneic tumors. Once these tumors reached clinically detectable size (500–800 mm(3)) they were treated by intra-tumoral injection with 3M-052 and/or CpG ODN. Anti-tumor immunity and tumor growth were evaluated. RESULTS: The co-delivery of agonists targeting TLRs 7, 8 and 9 increased the number and tumoricidal activity of tumor infiltrating CTL and NK cells while reducing the frequency of immunosuppressive MDSC. The combination of 3M-052 plus CpG ODN (but not each agent alone) eradicated large primary tumors and established long-term protective immunity. CONCLUSION: The combination of agonists targeting TLRs 7/8 and 9 represents a significant improvement in cancer immunotherapy.