Abstract
The receptor tyrosine kinase KIT is an established oncogenic driver of tumor growth in certain tumor types, including gastrointestinal stromal tumors, 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 antitumor effects of an inhibitory KIT mAb, dosed either alone or in combination with immune checkpoint inhibitors. Anti-KIT mAb treatment enhanced the antitumor activity of anti-CTLA-4 and anti-PD-1 mAbs, and promoted immune responses by selectively reducing the immunosuppressive monocytic myeloid-derived suppressor cell population and by restoring CD8+ and CD4+ T-cell populations to levels observed in naĆÆve 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. Mol Cancer Ther; 16(4); 671-80. Ā©2017 AACR.
Highlights
KIT (c-KIT, CD117, stem cell factor receptor) is a member of the type III receptor tyrosine kinase family, whose structure comprises five extracellular immunoglobulin (Ig)-like domains, a single transmembrane domain, and intracellular kinase catalytic and regulatory domains [1]
Our results demonstrate that treatment with an anti-KIT mAb profoundly reduces the immunosuppressive monocytic myeloid-derived suppressor cells (M-MDSC) population of tumor-bearing mice, resulting in enhanced antitumor efficacy of immune checkpoint inhibitors
The critical role of MDSC populations in limiting antitumor immune responses is increasingly apparent, and identification of www.aacrjournals.org novel approaches to target MDSC populations has become a key goal for new cancer therapeutics discovery [49]
Summary
KIT (c-KIT, CD117, stem cell factor receptor) is a member of the type III receptor tyrosine kinase family, whose structure comprises five extracellular immunoglobulin (Ig)-like domains, a single transmembrane domain, and intracellular kinase catalytic and regulatory domains [1]. The ligand for KIT, stem cell factor (SCF), activates the receptor by binding to the second and third Ig-like domains, thereby inducing receptor homodimerization, autophosphorylation, and activation of downstream signaling pathways [2, 3]. The identification of key interactions that contribute to receptor homodimerization within the fourth Ig-like domain (D4) of KIT suggested a novel approach to inhibit KIT function by targeting this region of the receptor [4], enabling structure-based design of KTN0158, a humanized anti-KIT IgG1 mAb. KTN0158 is currently undergoing human clinical trials in cancer patients (phase 1 study: NCT02642016). Current addresses: 1Kolltan Pharmaceuticals Inc., New Haven, Connecticut; 2Celldex Therapeutics, New Haven, Connecticut; 3Kleo Pharmaceuticals, New Haven, Connecticut; 4Alexion Pharmaceuticals, New Haven, Connecticut
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
