Enhancing Tumor Immunity: The Role of INCB081776 in Targeting AXL/MER Kinases

The TAM family of receptor tyrosine kinases, including Tyro-3, Axl, and Mer, are implicated in cancer progression and immune regulation. These kinases are often dysregulated in various cancers, contributing to tumor growth, survival, and resistance to therapies. They also play a role in innate immunity and immune-suppressive activity. INCB081776 is a novel inhibitor targeting Axl and Mer kinases, which has been developed to impact both the tumor's malignant progression and enhance the host's immune response against cancer.

In biochemical assays, INCB081776 demonstrated potent inhibition of Axl and Mer kinase activity, with high selectivity against a panel of 192 kinases. The inhibitor showed effectiveness in cellular assays, blocking auto-phosphorylation of Axl or Mer in various cell lines with low nanomolar IC50 values. Importantly, INCB081776 partially reversed the suppression of T cell proliferation by M2 macrophages and increased IFN-γ production in co-cultured macrophages and T cells.

In vivo studies in H1299 tumor-bearing mice showed that INCB081776 administration dose-dependently inhibited phosphorylation in tumors and potently inhibited tumor growth in immunocompetent mice, but not in immunodeficient mice, highlighting the importance of an intact immune system for its activity. The treatment led to an increase in tumor-infiltrating effector CD4+ and CD8+ T cells and macrophages with the M1 phenotype, while decreasing the presence of intratumoral M2 macrophages and monocytic myeloid-derived suppressor cells (M-MDSCs).

Combining INCB081776 with anti-PD-L1 in the 4T1 model resulted in synergistic anti-tumor effects. These preclinical findings support the potential of INCB081776 as an immunotherapeutic agent that could enhance tumor immune surveillance, both as a standalone treatment and in combination with immune checkpoint blockade therapies.