Abstract 3969: TP-0903, a potent AXL receptor tyrosine kinase inhibitor, enhances the activity of anti-PD-1 therapy in a metastatic preclinical syngeneic model of breast cancer (2019)

The high rate of non-responders to immune checkpoint inhibitors (ICI) represents significant challenges in the field of immune-oncology. Breast cancer has emerged as a cancer type that responds poorly to ICI. Therefore, there is an urgent need to better understand how cancer cells escape immune surveillance and resist immune attacks. Cancer cell clones with mesenchymal features seem to be less susceptible to attacks by immune cells. Hence, epithelial-to-mesenchymal transition (EMT) targeting agents such as TP-0903 are emerging as potential combination candidates to enhance immune checkpoint inhibition. AXL is overexpressed in a variety of cancers, often driving the pathogenesis and progression of disease. AXL overexpression induces cancer growth, invasion, metastasis, drug resistance, and mesenchymal characteristics. Aside from cancer cells, AXL is also expressed on several types of immune cells including macrophages and dendritic cells. Recently, it has been reported that AXL plays an important role as a negative regulator of immune response, contributing to an anti-tumor immune suppression. We have previously identified TP-0903 to be a potent small molecule inhibitor of AXL (IC50=14 nM) capable of reversing EMT. In this study, we evaluated whether TP-0903 could enhance the ICB effect in an ICB-resistant triple negative, metastatic breast cancer mouse model (4T1). In the 4T1 syngeneic model, anti-PD-1 monotherapy failed to inhibit tumor growth indicating that this tumor is resistant to anti-PD-1 treatment. The combination of TP-0903 and anti-PD-1 resulted in statistically significant tumor growth inhibition versus TP-0903 monotherapy (p<0.05). We hypothesized that the combination effect was influenced by potential CD8+ T cell depletion, and further investigated the effects of TP-0903 on immune cells in spleen and tumors. Tumor growth inhibition was found to be associated with a decrease in myeloid-derived suppressor cells (MDSC) in the spleen and an increase in infiltration and activation of dendritic cells (DCs) in the tumor. Gene expression analysis revealed that TP-0903 treatment decreased multiple immunosuppressive cytokines and chemokines including IL-6 and G-CSF in vivo. These results suggest that TP-0903 modulates the immune-suppressive tumor microenvironment (TME) to reinvigorate T cell immunity in anti-PD-1 resistant 4T1 tumors. In conclusion, AXL inhibition with TP-0903 modulates TME and enhances the anti-tumor effects of ICBs in an anti-PD-1 resistant, metastatic breast cancer mouse model. These findings support additional clinical testing of TP-0903 in combination with ICBs, which is currently being investigated in patients with advanced solid tumors in an ongoing clinical study (NCT02729298).Citation Format: Yuka Kumagai, Jun Oishi, Megumi Nakamura, Jason M. Foulks, Clifford J. Whatcott, Steven L. Warner, David J. Bearss, Masashi Goto. TP-0903, a potent AXL receptor tyrosine kinase inhibitor, enhances the activity of anti-PD-1 therapy in a metastatic preclinical syngeneic model of breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3969.