Immunomodulation

TriSalus’ multi-pronged approach is evaluating tumor-directed delivery of immunotherapeutic agents to the site of the disease. Our goal is to reprogram the tumor microenvironment, overcome immunosuppression, activate the immune system, and enable immunotherapy success in liver metastases and pancreatic solid tumors.

Vascular Solid Stress
Interstitial Fluid Pressure

Tumor microenvironment
Proliferation of tumor matrix compresses blood vessels, resulting in reduced or no flow

Challenges in Solid Tumor Treatments

Two critical barriers have been limiting immunotherapy advances in many solid tumor indications. Firstly, drug delivery into high pressure solid tumors with conventional delivery approaches is highly inefficient.1 Secondly, liver and pancreas tumors contain an abundance of suppressive cells that can shut down anti-tumor immunity and prevent durable responses to immunotherapy treatments.2,3 These problems cannot be addressed in isolation – a comprehensive solution is needed.

Therapeutic agents using current methods simply cannot adequately penetrate the tumor. When tumors grow in body cavities or solid organs, stroma is created, which includes connective tissue, blood vessels, and inflammatory cells, all of which are interposed between cancer cells and normal tissues. This stroma is very dense and can compress blood vessels, creating a high-pressure environment that limits therapy uptake into the tumor.4,5 Many cancers also have a way of turning off the body’s immune system that would otherwise aid in fighting and slowing the progression of the cancer.6 Additionally, by focusing delivery of immunotherapeutic agents into the vascular beds of liver or pancreas tumors, the goal is to minimize exposure to off-target organs providing a higher safety margin.

Intravascular Approach of Combination Treatment Research to Enhance the Responsiveness of Solid Tumors to Immunotherapy

A cold tumor is a solid mass of cells unresponsive to immunotherapy and complicated by dense stroma, creating formidable barriers to therapeutic delivery.7 Many solid tumors are considered unresponsive, including most tumors in the liver and pancreas.8 Importantly, each organ has specific immunosuppressive pathways that render therapies less effective.9,10 Myeloid-Derived Suppressor Cells (MDSCs) are a major driver of immunosuppression in the liver and pancreas. Through combining immunotherapeutic agents with our delivery technology, we hope to enable better outcomes in liver and pancreas cancer patients treated with checkpoint inhibitors and cell therapies.

The TriSalus approach has the potential for effective and safe delivery of immunomodulation therapy or other tumor killing agents that may induce T cell infiltration by changing the local microenvironment and has the potential to convert immunologically unresponsive tumors into responsive tumors.

Immunomodulation Diagram

The goal of TriSalus’ FDA cleared intravascular regional delivery technology is to help overcome the infusion barriers of the tumor microenvironment to deliver immunotherapeutic agents directly to the site of diseaseWhile our initial development focus will be uveal melanoma liver metastases, we plan to leverage our comprehensive immunotherapeutic approach in other liver and pancreas indications.

References:

  1. Wilhelm, S. et al. Analysis of nanoparticle delivery to tumours. Nat. Rev. Mater. 1, 16014 (2016).
  2. Feig, C. et al. The Pancreas Cancer Microenvironment. Clin. Cancer Res. 18, 4266–4276 (2012).
  3. Marabelle, A., Tselikas, L., de Baere, T. & Houot, R. Intratumoral immunotherapy: using the tumor as the remedy. Ann. Oncol. 28, xii33–xii43 (2017).
  4. Arneth, B. Medicina. 2020;56,15.
  5. Ryan, D.P., et al. New England Journal of Medicine. 2014;371(11):1039–1049.
  6. Srivastava, S., et al. J Immunol. 2018 Jan 15;200(2):459–468.
  7. Li J., Byrne K.T., et al. Immunity. 2018;49:178-193.
  8. Cavallo, J. The ASCO Post. 2019 Feb 10. https://ascopost.com/issues/february-10-2019/turning-cold-tumors-into-hot-ones/
  9. Ghosh, A., Gheorghe, D. Cell and Gene. 2019 Sept 26.
  10. Ma, S., et al. Int J Biol Sci. 2019;15(12):2548–2560.