Signaling via the AXL receptor tyrosine kinase is a key suppressor of anti-tumor innate immune response. AXL is expressed on several cells associated with the suppressive tumor immune microenvironment including natural killer cells, dendritic cells and tumor-associated macrophages. AXL is also an important regulator of tumor plasticity related to epithelial-to-mesenchymal transition (EMT) that contributes to anti-tumor immune evasion. Hence AXL signaling contributes uniquely to tumor intrinsic and microenvironmental immune suppression in tumors. We therefore evaluated whether blocking AXL signaling with BGB324, a selective clinical-stage small molecule Axl kinase inhibitor, enhances the effect of immune checkpoint blockade in syngeneic cancer mouse models that display limited immunogenicity.
We measured the effect of BGB324 in combination with anti-CTLA-4 and anti-PD-1 in the mammary adenocarcinoma 4T1/Balb/C syngeneic mouse model. BGB324 (50 mg/kg bid) significantly enhanced responsiveness to anti-CTLA-4/anti-PD-1 treatment (10 mg/kg of each, 4 doses) in Balb/C mice bearing 4T1 tumors. The combination of BGB324 + anti-CTLA-4/anti-PD-1 resulted in complete tumor clearance in 46.1 % of mice versus complete tumor clearance in 11.7 % of the mice treated with anti-CTLA-4/anti-PD-1 (p = 0.0087). BGB324 + anti-CTLA-4/anti-PD-1 treated tumors displayed enhanced CD8+ T cell tumor infiltration. Combination of BGB324 with immune checkpoint inhibitors is being evaluated in additional models, and detailed interrogation of AXL-dependent immune effector cell activity in tumors is in progress.
In conclusion, AXL inhibition represents a unique opportunity to target anti-tumor immune suppressive mechanisms and supports clinical translation of BGB324 in combination with cancer immunotherapy in human cancer.
Citation Format: Gro Gausdal, Kjersti Davidsen, Katarzyna Wnuk-Lipinska, Kathleen Wiertel, Monica Hellesøy, Magnus Blø, Lavina Ahmed, Linn Hodneland, Sergej Kiprijanov, Rolf A Brekken, James B Lorens. BGB324, a selective small molecule inhibitor of the receptor tyrosine kinase AXL, enhances immune checkpoint inhibitor efficacy. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr B014.
- ©2016 American Association for Cancer Research.