sTLT-1’s role in the tumor microenvironment

sTLT-1 is released by activated platelets and is found in high levels around solid tumors in the TME where it is actively involved in suppressing the innate immune system.1 It is not normally found in the plasma of healthy individuals but is linked to cancer and other diseases, such as cardiovascular disease2 and sepsis.3

In the presence of sTLT-1, monocytes tend to differentiate into M2-like macrophages and immature dendritic cells, which promote tumor growth. sTLT-1 induces immunosuppression through binding to CD11b receptors that are expressed on innate myeloid cells.

 

sTLT-1 binding to the extended CD11b receptor on innate myeloid cells suppresses the immune action of dendritic cells and macrophages

As solid tumors grow, they can induce the release of sTLT-1 to drive immune suppression. sTLT-1 levels are higher in cancer primary sites than in non-cancerous tissue and the concentration is inversely and extremely significantly correlated with cancer survival probability rates (Figure 1).

Figure 1. Data obtained from UCSC Xena, an open-source data tool (Pro-T refers to sTLT-1).

Ascendo’s innate ICI works by blocking sTLT-1

ASD141 blocks sTLT-1 from binding to Mac-1 and therefore prevents sTLT-1 binding on the extended Mac-1 receptor.

ASD141 is a novel innate immune checkpoint inhibitor (ICI) that blocks sTLT-1 from binding to the extended form of CD11b to reinvigorate the PRR pathways of inflammation and increase the numbers of immune-active, innate immune cells in the TME.1 Treatment with ASD141 normalizes immune-suppressive phenotypes induced by sTLT-1.1 By releasing the momentum of the innate immune system, the immune response can then be controlled and facilitated, thereby activating the cytotoxic T cells in a better orchestrated way.4,5,6,7

Recent results using ASD141 as a monotherapy include:

  • 24% reduction in tumor growth in MC38 murine colon cancer models.
  • 40% reduction in A459 human lung cancer in humanized mouse models.1

For more information on the research evidence see our ASD141 page.

A novel approach for the treatment of solid tumors, ASD141

References

  1. Ascendo unpublished data.
  2. Bayron, Z et al. Soluble Triggering Receptor Expressed on Myeloid Cells Like Transcript-1 (sTLT-1) as a Biomarker for Stable Cardiovascular Diseases [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2).
  3. Washington, AV et al. TREM-like transcript-1 protects against inflammation-associated hemorrhage by facilitating platelet aggregation in mice and humans. J Clin Invest. 2009; 119 (6):1489-1501.
  4. Haslam, A, Prasad, V. Estimation of the Percentage of US Patients With Cancer Who Are Eligible for and Respond to Checkpoint Inhibitor Immunotherapy Drugs. JAMA Netw Open. 2019; 2 (5): e192535.
  5. Jenkins, R et al. Mechanisms of resistance to immune checkpoint inhibitors. Br J Cancer. 2018; 118: 9–16.
  6. Hee TS et al. Cytokine Release Syndrome in Cancer Patients Receiving Immune Checkpoint Inhibitors: A Case Series of 25 Patients and Review of the Literature. Frontiers in Immunology. 2022; 13.
  7. Shimabukuro-Vornhagen A et al. Cytokine release syndrome. Journal for ImmunoTherapy of Cancer. 2018; 6: 56.

Interested in being part of our journey?

We are continuing our investigation into the immune suppressive effects of sTLT-1, its interplay with CD11b, the potential benefits of innate ICIs and the development of ASD141 as a clinical treatment for a range of solid tumors.

We are actively seeking partners and investors to accelerate the development of ASD141 as we move towards Phase I clinical trials. Contact our team for more information if you are interested in co-development or licensing opportunities.

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