Regional Delivery of Oligodeoxynucleotides (ODN2395) Showed Activation of Toll-Like Receptor Agonist in Mice
Ineffective Delivery May Be a Barrier to Achieving Clinical Success for Toll-Like Receptor Agonists in Certain Clinical Settings
TriSalus Life Sciences®, an emerging immuno-oncology company committed to transforming outcomes for patients with liver and pancreatic tumors, today announced data presented at the American Association of Cancer Research showing that regional delivery of oligodeoxynucleotide 2395 (ODN2395) activated the toll-like receptor 9 (TLR9), resulting in reduced tumor burden of liver metastases in mice.1
ODNs bind and activate TLR9 to initiate an immune response against certain cancer cells.2 TLR9 agonists (TLR9A) activate both the innate and adaptive immune systems, and play an important role in antiviral and anti-tumor immunity.3 TLR agonists have been administered via different routes based on the therapeutic purpose, however, delivery of TLR agonists into liver tumors by direct needle injection has been clinically challenging, particularly in the setting of a large tumor burden.
The pre-clinical study presented at AACR, conducted by Chandra C. Ghosh and fellow researchers at Roger Williams Medical Center, examined the impact of metastatic liver disease in 12 mice, which were randomized to receive either 1, 3, 10 or 30 micrograms of the TLR9A, ODN2395, through the portal vein (PV) or 30 micrograms administered intravenously (IV). The study showed regional delivery of the TLR9A through the PV at the 30 micrograms dose level was superior to systemic IV administration with respect to control of liver metastases and reduction of liver myeloid-derived suppressor cells (MDSC), which play a crucial role in solid tumor immunosuppression, in addition to favorable effects on liver macrophage subsets.
"Understanding the impact of delivery route on the ability of TLR9 agonists to control liver metastases and favorably modulate the immune microenvironment may help unleash the potential to use the immune system to fight cancer," said Steven Katz, M.D., Chief Medical Officer, TriSalus Life Sciences. "This foundational work will help us tap into the potential of integrating novel therapeutics with drug delivery technology to better penetrate solid tumors."
Solid tumors continue to represent one of the single biggest hurdles to successful cancer treatment.4 High levels of pressure inside solid tumors prevent the delivery of oncology therapeutics, with less than 1% of therapy penetrating solid tumors in some circumstances.5,6 TriSalus developed PEDD to deliver immuno-oncology therapeutics directly into the vasculature of solid tumors with the potential for minimizing systemic toxicity.
TriSalus Life Sciences is a revenue generating, emerging immuno-oncology company dedicated to developing immunotherapy treatments for liver and pancreatic tumors using novel delivery technologies to improve patient outcomes. TriSalus intends to pursue multiple solid tumor indications with investigational SD-101 and acquire other immuno-oncology agents to combine with its proprietary Pressure-Enabled Drug Delivery technology for the administration of therapeutics intravascularly into visceral organ solid tumors. In combination with checkpoint inhibitors, TriSalus’ focus is to reprogram the dominant immunosuppressive cell population in liver and pancreatic tumors. This innovative approach in development has the potential to leverage multiple mechanisms that can work together with the goal to overcome inherent immune suppression within the solid tumor microenvironment.
For more information, please visit www.trisaluslifesci.com.
Gosh, Chandra S. et al. Regional administration of Class C CpG Oligodeoxynucleotides results in superior intrahepatic TLR9 activation and immunomodulation compared to systemic infusion. AACR Poster April, 2021.
Shirota, Hidekazu, and Dennis M. Klinman. 2012. "Effect of CpG ODN on Monocytic Myeloid Derived Suppressor Cells." Oncoimmunology 1 (5): 780–82.
Krieg, Arthur M. 2007. "Development of TLR9 Agonists for Cancer Therapy." The Journal of Clinical Investigation 117 (5): 1184–94.
Jain, Rakesh K. 1994. "Barriers to Drug Delivery in Solid Tumors." Scientific American, 8.
Wilhelm, Stefan, Anthony J. Tavares, Qin Dai, Seiichi Ohta, Julie Audet, Harold F. Dvorak, and Warren C. W. Chan. 2016. "Analysis of Nanoparticle Delivery to Tumours." Nature Reviews Materials 1 (5): 16014. https://doi.org/10.1038/natrevmats.2016.14.
Sheth, Rahul A., Robin Hesketh, David S. Kong, Stephan Wicky, and Rahmi Oklu. 2013. "Barriers to Drug Delivery in Interventional Oncology." Journal of Vascular and Interventional Radiology 24 (8): 1201–7. https://doi.org/10.1016/j.jvir.2013.03.034.
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