pf-06463922 and Carcinoma--Pancreatic-Ductal

Pancreatic ductal adenocarcinoma (PDAC) patients have a 5-year survival rate of only 8% largely due to late diagnosis and insufficient therapeutic options. Neutrophils are among the most abundant immune cell type within the PDAC tumor microenvironment (TME), and are associated with a poor clinical prognosis. However, despite recent advances in understanding neutrophil biology in cancer, therapies targeting tumor-associated neutrophils are lacking. Here, we demonstrate, using pre-clinical mouse models of PDAC, that lorlatinib attenuates PDAC progression by suppressing neutrophil development and mobilization, and by modulating tumor-promoting neutrophil functions within the TME. When combined, lorlatinib also improves the response to anti-PD-1 blockade resulting in more activated CD8 + T cells in PDAC tumors. In summary, this study identifies an effect of lorlatinib in modulating tumor-associated neutrophils, and demonstrates the potential of lorlatinib to treat PDAC.

Topics: Aminopyridines; Animals; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; CD8-Positive T-Lymphocytes; Cell Line, Tumor; Disease Models, Animal; Drug Synergism; Female; Humans; Immune Checkpoint Inhibitors; Lactams; Lactams, Macrocyclic; Lymphocyte Activation; Lymphocytes, Tumor-Infiltrating; Male; Mice; Mice, Transgenic; Neutrophils; Pancreatic Neoplasms; Programmed Cell Death 1 Receptor; Pyrazoles; Tumor Microenvironment