(So many moving parts! I could have chosen an easier company.)
A close friend is on the scientific advisory board, didn't have a clue re. company or friend's assn........
meryxpharma.com
Company has good taste in consultants.
JCI Insight. 2018 Nov 2;3(21). pii: 97941. doi: 10.1172/jci.insight.97941. [Epub ahead of print]
MERTK inhibition alters the PD-1 axis and promotes anti-leukemia immunity.
Lee-Sherick AB1, Jacobsen KM2,3,4, Henry CJ3,4, Huey MG3,4, Parker RE3,4, Page LS1, Hill AA1, Wang X5, Frye SV5,6, Earp HS6,7, Jordan CT8, DeRyckere D3,4, Graham DK3,4.
1
Department of Pediatrics.
2
Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
3
Department of Pediatrics, Emory University, Atlanta, Georgia, USA.
4
Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Atlanta, Georgia, USA.
5
Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy.
6
Lineberger Comprehensive Cancer Center, and.
7
Departments of Medicine and Pharmacology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.
8
Division of Hematology, University of Colorado, Aurora, Colorado, USA.
MERTK is ectopically expressed and promotes survival in acute lymphoblastic leukemia (ALL) cells and is thus a potential therapeutic target. Here we demonstrate both direct therapeutic effects of MERTK inhibition on leukemia cells and induction of anti-leukemia immunity via suppression of the coinhibitory PD-1 axis. A MERTK-selective tyrosine kinase inhibitor, MRX-2843, mediated therapeutic anti-leukemia effects in immunocompromised mice bearing a MERTK-expressing human leukemia xenograft. In addition, inhibition of host MERTK by genetic deletion (Mertk-/- mice) or treatment with MRX-2843 significantly decreased tumor burden and prolonged survival in immune-competent mice inoculated with a MERTK-negative ALL, suggesting immune-mediated therapeutic activity. In this context, MERTK inhibition led to significant decreases in expression of the coinhibitory ligands PD-L1 and PD-L2 on CD11b+ monocytes/macrophages in the leukemia microenvironment. Furthermore, although T cells do not express MERTK, inhibition of MERTK indirectly decreased PD-1 expression on CD4+ and CD8+ T cells and decreased the incidence of splenic FOXP3+ Tregs at sites of leukemic infiltration, leading to increased T cell activation. These data demonstrate direct and immune-mediated therapeutic activities in response to MERTK inhibition in ALL models and provide validation of a translational agent targeting MERTK for modulation of tumor immunity. |
