title: Anti-KIT Monoclonal Antibody Treatment Enhances the Antitumor Activity of Immune Checkpoint Inhibitors by Reversing Tumor-Induced Immunosuppression.
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 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.Mol Cancer Ther; 16(4); 671-80. ©2017 AACR.
authors.affiliation: Kolltan Pharmaceuticals Inc., New Haven, Connecticut.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Garton
authors.affiliation: Kolltan Pharmaceuticals Inc., New Haven, Connecticut.
authors.forename: Scott
authors.initials: S
authors.lastname: Seibel
authors.affiliation: Kolltan Pharmaceuticals Inc., New Haven, Connecticut.
authors.forename: Lori
authors.initials: L
authors.lastname: Lopresti-Morrow
authors.affiliation: Kolltan Pharmaceuticals Inc., New Haven, Connecticut.
authors.forename: Linda
authors.initials: L
authors.lastname: Crew
authors.affiliation: Kolltan Pharmaceuticals Inc., New Haven, Connecticut.
authors.forename: Neal
authors.initials: N
authors.lastname: Janson
authors.affiliation: Kolltan Pharmaceuticals Inc., New Haven, Connecticut.
authors.forename: Sreekala
authors.initials: S
authors.lastname: Mandiyan
authors.affiliation: Kolltan Pharmaceuticals Inc., New Haven, Connecticut.
authors.forename: E Sergio
authors.initials: ES
authors.lastname: Trombetta
authors.affiliation: Kolltan Pharmaceuticals Inc., New Haven, Connecticut.
authors.forename: Shannon
authors.initials: S
authors.lastname: Pankratz
authors.affiliation: Kolltan Pharmaceuticals Inc., New Haven, Connecticut.
authors.forename: Theresa M
authors.initials: TM
authors.lastname: LaVallee
authors.affiliation: Kolltan Pharmaceuticals Inc., New Haven, Connecticut. rgedrich@celldex.com.
authors.forename: Richard
authors.initials: R
authors.lastname: Gedrich
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors*; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D004357:Drug Synergism; D006801:Humans; D007165:Immunosuppression Therapy; D051379:Mice; D000072737:Myeloid-Derived Suppressor Cells / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors*; D019009:Proto-Oncogene Proteins c-kit / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D019009:Proto-Oncogene Proteins c-kit