Overview

ASD141 is a novel, innate immune checkpoint inhibitor that commands the innate immune system to coordinate a renewed attack on solid tumors.

ASD141 works by:

Reinvigorating the cells that coordinate an immune response in the tumor microenvironment.

Improving the interface between innate and adaptive immunity.

Driving active antigen-presenting cells to the tumor environment.

Approximately 75% of patients do not respond to current immune checkpoint inhibitors (ICIs)1,2. By commanding a coordinated, innate immune response, ASD141 accesses a novel therapeutic route that could reach some of these patients.

The Challenge

As solid tumors grow, they can adopt mechanisms to suppress the immune system. One method is to induce the release of TLT-1 from platelets.7 TLT-1 binds to CD11b receptors on immature, innate myeloid cells in the tumor microenvironment and switches them to an immune suppressive state.3 By the time a tumor is detectable, the tumor microenvironment often contains high levels of immune suppressive cells and immune exhaustion has already set in.

Although ICIs have shown great success in treating some cancers by elevating an adaptive immune response through reactivated T cells, they only work for around 30% of cancer patients. Effective ICI therapy is not without its problems too, cytokine release syndrome (CRS)4 has been reported in around 4.6% of patients receiving ICIs5, where elevated levels of cytokines lead to immune hyperactivation with life-threatening consequences. Anti-CTLA4 therapy has also been linked to autoimmune disease through the depletion of regulatory T cells6.

The main challenge for ICI therapy is that the drug acts directly on the adaptive immune system bypassing the mediation by the innate immune system. When drugs are used to directly amplify the numbers and activation of T cells, unchecked, overactivation can occur.

The Solution

ASD141 is a unique approach to driving immune activation in the tumor microenvironment. It is a novel ICI that commands an active, innate immune response to solid tumors, by targeting the very cells that control the immune reaction.

ASD141 works by blocking TLT-1, thereby reversing immune suppression. Increased numbers of active, mature antigen-presenting cells are driven to the tumor microenvironment to coordinate an orchestrated immune attack. Through the action of the innate channel, adaptive immunity is normalized, activated and directed to destroy cancer cells.

The Evidence

ASD141 has shown a reduction in tumor growth (tumor growth inhibition [TGI]) by 24% in MC38 murine colon cancer models and by 40% in A549 human lung cancer humanized mouse model as a monotherapy:

Reduced immuno-supressive myeloid cells

Immune-suppressive myeloid cells were reduced by 10.4% in the MC38 tumor microenvironment.

Increased co-stimulatory molecules

Significantly increased expression of co-stimulatory molecules CD80/CD86 and class II major histocompatibility complex molecules (MHC class II) increased in myeloid cells, indicating an enhanced immune response through increased levels of antigen presenting Cells (APCs).

Increased number of tumor-reactive T cells

Increase of cytotoxic CD8 T cell compared to control (5.11% to 8.52%) and interferon-gamma (IFN-γ) (3.31% to 6.32%), indicating activation of cytotoxic T cells and increased number of tumor-reactive T cells.

More active, mature dendritic cells

Active, mature, IL-12 producing dendritic cells (a type of antigen-presenting cell) increased up to 10-fold in the MC38 tumor microenvironment.

More anti-neoantigen specific cytotoxic T cells

Two-fold increase of 4-1BB+ (CD137) detected in CD8 T cells (1.5% to 2.99%), indicating increased anti-neoantigen-specific cytotoxic T cells in the MC38 tumor microenvironment.

“We are breaking through the limitations of current immunotherapies to enable access for more patients than ever before.”

Dr. Yen-Ta Lu / Founder and Chief Scientific Officer of Ascendo

The Application

According to the World Health Organization, 9.6 million people died from cancer in 2018. Although there have been enormous leaps in treating and even providing cures for some types of cancer, such as estrogen-receptor-positive breast cancer, melanomas and testicular cancer, we are a long way from providing cures for many types.

Even with the successes seen in ICI therapy, approximately 75% of patients will not respond1,2. Clearly, novel therapeutic routes need to be explored and, currently, the innate route and its research are underutilized. The innate pathway holds the potential to deliver better regulation of the natural immune response to cancer by activating natural control pathways.

There is a direct correlation between high concentrations of TLT-1 in the tumor microenvironment and poor prognosis. ASD141 provides a novel route to activate a controlled innate immune response that could destroy solid tumors by preventing immune exhaustion likely to be driven by TLT-1.

Presence of TLT-1 (Pro-T) in primary cancer sites and correlation between TLT-1 (Pro-T) and survival probability

Figure 1. Data obtained from UCSC Xena, an open-source data tool.

The Future

We are actively seeking potential pharmaceutical partners and investors to accelerate the development of ASD141 and look forward to initiating phase I clinical trials for safety and efficacy studies and we are evaluating business partners for co-development and licensing.

References

  1. Schoenfeld, Adam J., and Matthew D. Hellmann. “Acquired resistance to immune checkpoint inhibitors.” Cancer cell 37.4 (2020): 443-455. https://doi.org/10.1016/j.ccell.2020.03.017
  2. 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. doi:10.1001/jamanetworkopen.2019.2535
  3. Ascendo unpublished data
  4. Shimabukuro-Vornhagen, Alexander et al. Cytokine release syndrome. Journal for immunotherapy of cancer vol. 6,1 56. 15 Jun. 2018. doi:10.1186/s40425-018-0343-9
  5. Tay Sen Hee 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. doi: 10.3389/fimmu.2022.807050
  6. Bertrand A, Kostine M, Barnetche T, Truchetet ME, Schaeverbeke T. Immune related adverse events associated with anti-CTLA-4 antibodies: systematic review and meta-analysis. BMC Med. 2015 Sep 4;13:211. doi: 10.1186/s12916-015-0455-8
  7. Chen, X, Song, E. The theory of tumor ecosystem. Cancer Commun. 2022; 1– 22. https://doi.org/10.1002/cac2.12316

Interested in being part of our journey?

We are interested in hearing from partners who are interested in co-developing or licensing ASD141 or investors who are interested in being part of this journey.

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