Recent breakthroughs have demonstrated that patients with advanced forms of cancer can be effectively treated by selective activation of the immune system. While these extraordinary findings have highlighted the power of immuno-oncology, current medications are only effective in a minority of patients and in a subset of cancers. As a result, there has been growing interest in approaches that can enhance the power of the immune system to benefit more patients and more forms of cancer. Tilos Therapeutics is bringing new insights and tools to this effort. Tilos’s anti-LAP antibodies have the potential to transform cancer therapy through transformation of the tumor microenvironment.
Cancer cells thrive in environments where they are protected from detection and attack by tumor-specific immune cells. The tumor microenvironment is rich in inhibitory cell populations, including Tregs, MDSCs and TAMS. They are also rich in the inhibitory mediators that are made by these cells and also produced by the tumors themselves: TGFβ, IL-10, IDO, arginase and others. Together, these cells and mediators create a milieu that inhibits priming of antigen-specific T cells, shuts down tumor-specific effector cells, spawns the growth of a dense extracellular matrix to exclude immune effectors, and induces epithelial-to-mesenchymal transition, a key early step in metastasis. Therapeutics that can transform the tumor microenvironment and open tumors up to attack by the immune system are a critical piece in the developing arsenal of cancer therapies.
LAP is a protein that forms a cage around TGFβ, holding the potent cytokine in a latent state until it is ready to be deployed. Cells that use TGFβ as part of their immunosuppressive toolbox express the LAP-TGFβ complex on their cell surface. Anti-LAP antibodies are able to bind to multiple cell populations of importance in the tumor microenvironment – MDSCs, Tregs, and TAMs – targeting them for deletion. In addition, anti-LAP antibodies are designed to inhibit the release of TGFβ from the LAP-TGFβ complex, adding a second layer of functionality to these powerful antibodies.
TGFβ plays a key role in many aspects of tumor growth, including immunosuppression, epithelial-to-mesenchymal transition, angiogenesis, and metastasis. It is also a primary driver in fibrosis, playing a role both in primary fibrotic disease and in the growth of desmoplastic tumors. TGFβ is a labile, highly potent cytokine with a half-life in vivo of 2-3 minutes. While therapeutics targeting the mature cytokine must attempt to block its action during this short window, anti-LAP antibodies block the release of TGFβ at the source. We believe our approach opens up the opportunity to target this important cytokine with much greater efficiency, addressing key limitations of existing TGFβ therapies.
Tilos’s anti-LAP antibodies have the potential to treat a broad range of cancers, which includes head and neck squamous cell carcinoma, hepatocellular carcinoma, ovarian cancer, colorectal cancer, gastric cancer, and non-small cell lung cancer.