Title: Pan-TAM Tyrosine Kinase Inhibitor BMS-777607 Enhances Anti-PD-1 mAb Efficacy in a Murine Model of Triple-Negative Breast Cancer.

Authors: Kasikara, Canan; Davra, Viralkumar; Calianese, David; Geng, Ke; Spires, Thomas E; Quigley, Michael; Wichroski, Michael; Sriram, Ganapathy; Suarez-Lopez, Lucia; Yaffe, Michael B; Kotenko, Sergei V; De Lorenzo, Mariana S; Birge, Raymond B

Published In Cancer Res, (2019 05 15)

Abstract: Tyro3, Axl, and Mertk (TAM) represent a family of homologous tyrosine kinase receptors known for their functional role in phosphatidylserine (PS)-dependent clearance of apoptotic cells and also for their immune modulatory functions in the resolution of inflammation. Previous studies in our laboratory have shown that Gas6/PS-mediated activation of TAM receptors on tumor cells leads to subsequent upregulation of PD-L1, defining a putative PS→TAM receptor→PD-L1 inhibitory signaling axis in the cancer microenvironment that may promote tolerance. In this study, we tested combinations of TAM inhibitors and PD-1 mAbs in a syngeneic orthotopic E0771 murine triple-negative breast cancer model, whereby tumor-bearing mice were treated with pan-TAM kinase inhibitor (BMS-777607) or anti-PD-1 alone or in combination. Tyro3, Axl, and Mertk were differentially expressed on multiple cell subtypes in the tumor microenvironment. Although monotherapeutic administration of either pan-TAM kinase inhibitor (BMS-777607) or anti-PD-1 mAb therapy showed partial antitumor activity, combined treatment of BMS-777607 with anti-PD-1 significantly decreased tumor growth and incidence of lung metastasis. Moreover, combined treatment with BMS-777607 and anti-PD-1 showed increased infiltration of immune stimulatory T cells versus either monotherapy treatment alone. RNA NanoString profiling showed enhanced infiltration of antitumor effector T cells and a skewed immunogenic immune profile. Proinflammatory cytokines increased with combinational treatment. Together, these studies indicate that pan-TAM inhibitor BMS-777607 cooperates with anti-PD-1 in a syngeneic mouse model for triple-negative breast cancer and highlights the clinical potential for this combined therapy. SIGNIFICANCE: These findings show that pan-inhibition of TAM receptors in combination with anti-PD-1 may have clinical value as cancer therapeutics to promote an inflammatory tumor microenvironment and improve host antitumor immunity.

PubMed ID: 30877108

MeSH Terms: Aminopyridines/pharmacology*; Animals; Antibodies, Monoclonal/immunology*; Cell Line, Tumor; Disease Models, Animal; Female; Lymphocytes, Tumor-Infiltrating/immunology; Mice; Mice, Inbred C57BL; Programmed Cell Death 1 Receptor/immunology*; Protein-Tyrosine Kinases/antagonists & inhibitors*; Pyridones/pharmacology*; Triple Negative Breast Neoplasms/immunology; Triple Negative Breast Neoplasms/therapy*; Tumor Microenvironment/immunology; Xenograft Model Antitumor Assays