880 Inhibition of AXL signaling with AB801 augments anti-tumor immune responses

Background

AXL receptor tyrosine kinase (AXL) is overexpressed in a variety of tumors and correlates with poor prognosis in cancer patients. AXL is expressed in cancer, stromal, and select immune cells, and has been implicated in the development of resistance to immunotherapies, chemotherapy, and targeted therapies.^{1 2} AXL signaling creates an immunosuppressive tumor microenvironment (TME) via both tumor-intrinsic and immune-mediated mechanisms, fostering therapeutic resistance. AXL inhibition in combination with αPD-1 and/or chemotherapy overcomes therapeutic resistance and promotes robust anti-tumor responses in murine models.

Methods

Anti-tumor efficacy and tolerability of AB801 was assessed in murine syngeneic models in combination with αPD-1 and/or chemotherapy under conditions in which the tumors responded or were refractory to αPD-1 treatment. Immune profiling of tumors by flow cytometry and IHC was performed to determine changes in immune infiltration after single agent AB801 treatment and AB801 in combination with αPD-1 and/or chemotherapy. DNA damage after AB801 treatment in combination with chemotherapy was assessed by western and mRNA analyses.

Results

AB801 treatment increases sensitivity to multiple therapeutics, including immunotherapy and chemotherapy. In murine syngeneic tumors, AXL is expressed on tumor cells and select myeloid immune cells, including mregDC’s. Importantly, AB801 treatment sensitizes tumors to immune checkpoint blockade by increasing immune cell activation and infiltration while decreasing immunosuppressive cells in the TME. AB801 also enhances responses to chemotherapy by increasing DNA damage. Significant tumor growth inhibition, complete responses, including tumor regressions and increased survival are observed with AB801 treatment in combination with αPD-1 and chemotherapy in syngeneic models.

Conclusions

AXL is a promising therapeutic target involving both immunomodulatory and tumor-intrinsic mechanisms. The potent and selective AXL inhibitor AB801 reduces immunosuppression in the TME, enables activation of an anti-tumor immune responses, and renders tumors more susceptible to checkpoint blockade and chemotherapeutic treatment.

References