The AXL receptor tyrosine kinase is expressed by several tumor types and is associated with poor overall survival in patients. AXL signaling is an important regulator of tumor cell plasticity related to epithelial-to-mesenchymal transition (EMT) and stem cell traits that drive metastasis, drug resistance and immune evasion. AXL is also expressed on several cells associated with the inflammatory tumor immune microenvironment including natural killer (NK) cells, dendritic cells and tumor-associated macrophages. Signaling via AXL is a key suppressor of the anti-tumor innate immune response. Hence, AXL signaling contributes uniquely to tumor cell intrinsic and microenvironmental anti-tumor immune suppression mechanisms in cancer. We evaluated whether blocking AXL signaling with BGB324, a selective clinical-stage small molecule AXL kinase inhibitor, enhanced the effect of immune checkpoint blockade in aggressive adenocarcinomas that display limited immunogenicity.
Immune therapy with anti-PD-1/anti-PD-L1 or anti-CTLA-4/anti-PD-1 increased AXL and EMT-marker expression in the murine lung cancer (Lewis lung, LL2) and mammary adenocarcinoma (4T1) syngeneic models, and correlated with a lack of response to immune checkpoint therapy. Combination treatment with BGB324 (50 mg/kg bid) significantly enhanced responsiveness to anti-PD-1/anti-PD-L1 or anti-CTLA-4/anti-PD-1 treatment (10 mg/kg of each, 6 doses for LL2; 4 doses for 4T1) in mice bearing established LL2 or 4T1 tumors respectively. BGB324 in combination with anti-PD-1/anti-PD-L1 or anti-CTLA-4/anti-PD-1 enhanced tumor infiltration of cytotoxic T lymphocytes (CTLs). Increased CTLs were also detected in spleens from animals responding to treatment. BGB324 + anti-CTLA-4/anti-PD-1 combination treatment increased the number of NK cells, macrophages and polymorphonuclear neutrophils, but decreased the number of tumor-associated myeloid-derived suppressor cells (MDSC).
In the 4T1 model, the combination of BGB324 + anti-CTLA-4/anti-PD-1 resulted in durable primary tumor clearance in 23% of treated mice versus 5.6% obtained with anti-CTLA-4/anti-PD-1 alone (p = 0.0157). In a separate study, BGB324 + anti-CTLA-4 therapy treated resulted in 22% long-term primary tumor clearance while no response was observed with anti-CTLA4 treatment alone. The extensive metastasis to the lung, liver and spleen characteristic of this model was concomitantly abrogated in the animals responding to the combination treatment. Importantly, responding animals rejected orthotopic 4T1 tumor cell re-challenge, demonstrating sustained tumor immunity
These findings along with the favorable safety profile and clinical activity of BGB324 in ongoing monotherapy clinical trials, support a rationale for clinical testing of BGB324 in combination with immune checkpoint inhibitors in cancer patients.
Citation Format: Katarzyna Wnuk-Lipinska, Kjersti Davidsen, Magnus Blø, Linn Hodneland, Agnete Engelsen, Jing Kang, Maria Lie, Sebastien Bougnaud, Kristina Aguilera, Lavina Ahmed, Agata Rybicka, Elina Milde, Paulina Deyna, Anna Boniecka, Oddbjørn Straume, Salem Chouaib, Rolf Brekken, Gro Gausdal, James Lorens. BGB324, a selective small molecule inhibitor of AXL receptor tyrosine kinase, enhances immune checkpoint inhibitor efficacy [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B027.
- ©2016 American Association for Cancer Research.