The receptor tyrosine kinase KIT is an established oncogenic driver of tumor growth in certain tumor types including gastrointestinal stromal tumors (GIST), in which constitutively active mutant forms of KIT represent an actionable target for small molecule tyrosine kinase inhibitors. There is also considerable potential for KIT to influence tumor growth indirectly based on its expression and function in cell types of the innate immune system, most notably mast cells. We have evaluated syngeneic mouse tumor models for anti-tumor effects of an inhibitory KIT monoclonal antibody (mAb), dosed either alone or in combination with immune checkpoint inhibitors. Anti-KIT mAb treatment enhanced the anti-tumor activity of anti-CTLA-4 and anti-PD-1 mAbs, and promoted immune responses by selectively reducing the immunosuppressive monocytic myeloid-derived suppressor cell (M-MDSC) population and restoring CD8+ and CD4+ T-cell populations to levels observed in naïve mice. These data provide a rationale for clinical investigation of the human KIT-specific mAb KTN0158 in novel immuno-oncology combinations with immune checkpoint inhibitors and other immunotherapeutic agents across a range of tumor types.
- Received October 13, 2016.
- Revision received December 15, 2016.
- Accepted December 16, 2016.
- Copyright ©2017, American Association for Cancer Research.