Abstract 4020: Inhibition of KIT <i>in vivo</i> modifies immune cell populations to improve the efficacy of checkpoint inhibitors in syngeneic mouse tumor models
Authors: Andrew J. Garton, Lori Lopresti-Morrow, Scott Seibel, Theresa LaVallee, Richard Gedrich
Journal: Cancer Research (2016)

Abstract The KIT receptor tyrosine kinase plays critical roles in GIST and a range of other tumor types, and when activated by somatic mutation serves as a potent oncogenic driver in these neoplasms. Whereas small molecule inhibitors of the tyrosine kinase domain of KIT have demonstrated considerable success in treatment of GIST patients with some KIT mutations, there remains a need to develop additional KIT-directed therapies for treatment of GIST patients that fail to respond to these agents, or that develop resistance during therapy. Furthermore, KIT is prominently expressed on mast cells, which promote an immune evasive environment within the tumor microenvironment by influencing the function of other immune cells, such as myeloid derived suppressor cells (MDSC’s). However, the potential impact of KIT inhibition on anti-tumor immunity has not been studied extensively to date. KTN0158 is a humanized anti-KIT IgG1 monoclonal antibody that specifically binds to the extracellular domain of KIT, and is being developed as a potential therapy for cancer and other mast cell-related diseases such as neurofibromatosis type 1 (NF1). KTN0158 inhibits KIT signaling and function in vitro and in vivo and has demonstrated anti-tumor activity in dogs with mast cell tumors expressing either wild-type or mutant KIT. In order to explore the potentially broad anti-tumor benefit of KIT inhibition by an antibody, a series of syngeneic tumor models were evaluated for sensitivity and immune cell profile changes in response to a surrogate antibody that recognizes mouse KIT (ACK2), dosed as either a single agent or in combination with T cell checkpoint inhibitors. Within this panel of tumor models, ACK2 strongly enhanced the anti-tumor activity provided by an anti-CTLA4 antibody in the colon26 model, while exhibiting no anti-tumor activity when dosed as a single agent. The colon26 cell line does not express detectable levels of KIT, and does not exhibit sensitivity to ACK2 or SCF treatment in proliferation assays performed in vitro, suggesting that this effect of ACK2 is not due to a direct effect on the tumor cells. Strikingly, ACK2 treatment was associated with pronounced effects on immune cell populations, including a profound decrease in both intra-tumoral and splenic monocytic MDSC counts. These observations suggest that KIT inhibition in vivo has the potential to modulate immune cell populations including MDSC's and mast cells, thereby targeting immune suppressive innate immune cells in the tumor and sensitizing the tumor to immune checkpoint inhibitors. Furthermore, the data provide a rationale to investigate KTN0158 in combination with immune checkpoint inhibitors across a range of human tumor types. Citation Format: Andrew J. Garton, Lori Lopresti-Morrow, Scott Seibel, Theresa LaVallee, Richard Gedrich. Inhibition of KIT in vivo modifies immune cell populations to improve the efficacy of checkpoint inhibitors in syngeneic mouse tumor models. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4020.