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

By Gan Zhao1, John P Vasilakos2, Debra Tross1

  • 1Cancer and Inflammation Program, National Cancer Institute, NIH, Frederick MD 21702, USA.

Journal for Immunotherapy of Cancer
|July 2, 2014
PubMed
Abstract

Insights

Combining Toll-like receptor 7/8 agonist 3M-052 with Toll-like receptor 9 agonist CpG ODN eradicated large tumors and established long-term immunity in mice, improving cancer immunotherapy.

Area of Science:

  • Immunology
  • Oncology
  • Pharmacology

Background:

  • Toll-like receptor (TLR) agonists 3M-052 (TLR7/8) and CpG ODN (TLR9) induce innate immune responses beneficial for tumor-specific immunity.
  • Individual administration of these agonists showed limited efficacy against advanced tumors in prior studies.

Purpose of the Study:

  • To evaluate the efficacy of combining TLR7/8 and TLR9 agonists for cancer immunotherapy.
  • To assess the impact of combined TLR agonists on anti-tumor immunity and tumor growth in a murine model.

Main Methods:

  • Syngeneic tumors were established in normal mice.
  • Clinically detectable tumors (500-800 mm³) were treated with intra-tumoral injections of 3M-052 and/or CpG ODN.
  • Tumor growth and anti-tumor immune responses were analyzed.

Main Results:

  • Co-administration of 3M-052 and CpG ODN enhanced tumor-infiltrating cytotoxic T lymphocytes (CTL) and natural killer (NK) cells, increasing their tumoricidal activity.
  • The combination therapy significantly reduced the frequency of immunosuppressive myeloid-derived suppressor cells (MDSC).
  • Combined 3M-052 and CpG ODN eradicated large primary tumors and conferred long-term protective immunity, unlike individual treatments.

Conclusions:

  • The combination of TLR7/8 and TLR9 agonists represents a potent strategy for cancer immunotherapy.
  • Dual TLR agonist therapy overcomes limitations of single-agent treatments for advanced tumors.
Keywords:
CancerCpG ODNInnate immunityTLR agonistsTherapy

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