Toll-Like Receptor 9 Agonist

Toll-Like Receptor 9 (TLR9) Agonist: Stimulating TLR9 may promote anti-tumor activity by activating the immune system to help attack solid tumors and convert suppressive immune cells into more immunostimulatory subtypes.1,2

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TLR9 agonists convert MDSCs into immunostimulatory M1 macrophages,4 convert immature dendritic cells to mature dendritic cells,3 and expand effector T cells creating a responsive TME that may promote anti-tumor activity.3

It is believed Toll-Like receptors (TLR) play a key role in the innate immune system and create a bridge to adaptive immunity.2 Small studies have shown activating TLR9 primes immune cells to promote anti-tumor T cell function.2,3

 

TLR9 Agonists

TLR9 agonists may stimulate anti-tumor activity by reducing the number of myeloid-derived suppressor cells (MDSCs), which is believed to suppress the immune system in solid tumors.4,5 The myeloid-derived suppressor cell (MDSC) is thought to protect the cancer from the patient’s immune system allowing the tumor to thrive.6 It is proposed that these cells may limit the efficacy of immunotherapeutic agents in solid tumors due to their anti-inflammatory and immunosuppressive activity.7,8,9 Increasing TLR9 activity may lessen the impact of suppressive cells and convert them into immunostimulant cells.5,10 High levels of MDSCs have been observed in a number of cancers including liver, liver metastases, pancreatic cancer, and melanoma.7,11

Clinical studies are being conducted to determine if TLR9 agonists have the potential to be highly effective on their own when combined with PEDD™ in addition to enhancing the benefit of other immuno-oncology agents.

Leveraging TriSalus’ proprietary Pressure-Enabled Drug Delivery™ (PEDD™) approach for regional delivery of an investigational TLR9 agonist, which is being studied to enhance the therapeutic index for liver metastases and pancreatic cancers. TriSalus will initially evaluate an investigational TLR9 agonist, for the treatment of uveal melanoma liver metastases and for additional programs looking at combinations with other immuno-oncology agents delivered with PEDD.

References:

  1. Weihrauch, M.R., et al. Eur J Cancer. 2015;51(2):146‐156.
  2. Melisi, D., et al. Biomedicines. 2014;2(3):211‐228.
  3. Humbert, M., et al. Cancer Res. 2018;78(12):3280‐3292.
  4. Shirota, H., et al. Oncoimmunology. 2012;1(5):780‐782.
  5. Hossain, D.M., et al. Clin Cancer Res. 2015;21(16):3771‐3782.
  6. Tesi, R.J. Trends Pharmacol Sci. 2019;40:4-7.
  7. Katz, S.G., et al. Oncogene. 2019 Jan;38(4):533-548.
  8. Katz, S.G.., et al. Cancer Immunol Immunother. 2015 Jul;64(7):817-29.
  9. Katz, S.G., et al. Cancer Gene Ther. 2016 Jun;23(6):188-98.
  10. Zoglmeier, C., et al. Clin Cancer Res. 2017 Feb 15;23(4):1117] and Clin Cancer Res. 2011;17(7):1765‐1775.
  11. Shirota, Y., et al. J Immunol. 2012;188(4):1592‐1599.