Sitravatinib potentiates immune checkpoint blockade in refractory cancer models.

Abstract

Immune checkpoint blockade has achieved significant therapeutic success for a subset of cancer patients; however, a large portion of cancer patients do not respond. Unresponsive tumors are characterized as being immunologically "cold," indicating that these tumors lack tumor antigen-specific primed cytotoxic T cells. Sitravatinib is a spectrum-selective tyrosine kinase inhibitor targeting TAM (TYRO3, AXL, MerTK) and split tyrosine-kinase domain-containing receptors (VEGFR and PDGFR families and KIT) plus RET and MET, targets that contribute to the immunosuppressive tumor microenvironment. We report that sitravatinib has potent antitumor activity by targeting the tumor microenvironment, resulting in innate and adaptive immune cell changes that augment immune checkpoint blockade. These results suggest that sitravatinib has the potential to combat resistance to immune checkpoint blockade and expand the number of cancer patients that are responsive to immune therapy.

• Authors: Wenting Du, Huocong Huang, Noah Sorrelle, Rolf A Brekken
• Journal: JCI insight (JCI Insight) Vol. 3 Issue 21 (11 02 2018) ISSN: 2379-3708 [Electronic] United States
• PMID: 30385724 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Anilides
• Protein Kinase Inhibitors
• Pyridines
• sitravatinib

Topics

• Anilides (administration & dosage, pharmacology)
• Animals
• Clinical Trials as Topic
• Female
• Immunotherapy (methods, statistics & numerical data)
• Injections, Subcutaneous
• Macrophages (drug effects, immunology)
• Mice
• Mice, Inbred C57BL
• Neoplasms (drug therapy, immunology)
• Protein Kinase Inhibitors (pharmacology)
• Pyridines (administration & dosage, pharmacology)
• Tumor Microenvironment (drug effects)