The Multi-Kinase Inhibitor Lucitanib Enhances the Antitumor Activity of Coinhibitory and Costimulatory Immune Pathway Modulators in Syngeneic Models.

ABSTRACT

Lucitanib is a multi-tyrosine kinase inhibitor whose targets are associated with angiogenesis and other key cancer and immune pathways. Its antiangiogenic properties are understood, but lucitanib's immunomodulatory activity is heretofore unknown. Lucitanib exhibited such activity in vivo, increasing CD3 + , CD8 + , and CD4 + T cells and decreasing dendritic cells and monocyte-derived suppressor cells in mouse spleens. Depletion of CD8 + T cells from syngeneic MC38 colon tumor-bearing mice reduced the antitumor efficacy of lucitanib and revealed a CD8 + T-cell-dependent component of lucitanib's activity. The combination of lucitanib and costimulatory immune pathway agonists targeting 4-1BB, glucocorticoid-induced TNFR (GITR), inducible T-cell co-stimulator (ICOS), or OX40 exhibited enhanced antitumor activity compared with each single agent in immunocompetent tumor models. Lucitanib combined with blockade of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) or programmed cell death protein-1 (PD-1) coinhibitory immune pathways also showed enhanced antitumor activity over the single agents in multiple models. In CT26 tumors, lucitanib, alone or combined with anti-PD-1, reduced CD31 + vessels and depleted F4/80 + macrophages. Combination treatment also increased the number of intratumoral T cells. Gene expression in pathways associated with immune activity was upregulated by lucitanib in MC38 tumors and further potentiated by combination with anti-PD-1. Accordingly, lucitanib, alone or combined with anti-PD-1, increased intratumoral CD8 + T-cell abundance. Lucitanib's antitumor and pharmacodynamic activity, alone or combined with anti-PD-1, was not recapitulated by specific vascular endothelial growth factor receptor-2 (VEGFR2) inhibition. These data indicate that lucitanib can modulate vascular and immune components of the tumor microenvironment and cooperate with immunotherapy to enhance antitumor efficacy. They support the clinical development of lucitanib combined with immune pathway modulators to treat cancer.