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

  • J Immunother Cancer. 2014 May 13;2:12. doi: 10.1186/2051-1426-2-12.
By Gan Zhao  1 ,  John P Vasilakos  2 ,  Debra Tross  1 ,  Dmitri Smirnov  2 ,  Dennis M Klinman  1
Affiliations
  • 1. Cancer and Inflammation Program, National Cancer Institute, NIH, Frederick MD 21702, USA.
  • 2. 3M Drug Delivery Systems Division, St. Paul MN 55144, USA.
PMID: 24982761 DOI: 10.1186/2051-1426-2-12
Abstract

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.

Keywords
Cancer; CpG ODN; Innate immunity; TLR agonists; Therapy.
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