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 monocytederived 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-lymphocyteassociated 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.

Multifunctional Nano-Realgar Hydrogel for Enhanced Glioblastoma Synergistic Chemotherapy and Radiotherapy: A New Paradigm of an Old Drug

“…This finding indicates that the hypoxic state of tumors may be alleviated by NRA@DH Gel treatment by improving tumor oxygenation and enhancing the effect of NRA@DH Gel on radio-sensitization. In addition, IHC staining for CD31 and Ki-67 was performed to evaluate tumor angiogenesis, cell proliferation, and migration, 52 , 53 as shown in Figure 5C . As expected, CD31 and Ki-67 expression levels in tumors treated with NRA@DH Gel and RT were significantly lower compared to other treatments, indicating NRA@DH Gel inhibits cell proliferation and migration and has a suppressive effect on tumor microvasculature.…”

The anti-PD-1 era of cervical cancer: achievement, opportunity, and challenge

“…The reference mechanisms of anti-PD-1 combined with other therapeutic modalities. The anti-tumor effect of anti-PD-1 combined with other therapies was reflected in the activation of the tumor immune microenvironment, including activating effector T cells, polarizing M2 macrophages towards M1 type, and inhibiting Tregs function, etc., which together remodeling inhibitory TME (58)(59)(60)(61)(62)(63). For other therapies, the upregulation of interferon-stimulated genes (ISGs) gene expression induced by the JAK/STAT signaling pathway or cGSA/STING signaling pathway was the basis of association, such as the upregulation of PD-L1 or MHC I was the common feature (58,(64)(65)(66).…”

“…The study has shown that lenvatinib was critical for transforming macrophages to the M2 phenotype by targeting PKCα/ZFP64/CSF1 axis to trigger immune evasion and anti-PD-1 tolerance in a model of hepatocellular carcinoma ( 67 ). Moreover, the effect of angiogenesis inhibition of these TKI-VEGFR targeted drugs could also facilitate tumor vessel normalization by reducing CD31 + micro-vessels to regulate TME, which could be enhanced by anti-PD-1 further ( 61 , 76 ).…”

“…The activated TME was the key to exerting an anti-tumor effect, which was reflected in the increasing proportion of activated effector T cells and M1-type macrophages, the decreasing of Tregs, MDSCs, and M2-types macrophages. The secretion of cytokines also changes, including increased levels of IFN-g, TNFa, and IL-2 as well as decreased levels of TGFb and IL-6 (58)(59)(60)(61)(62). The studies have demonstrated that chemotherapies and targeted therapies could activate TME through different ways to synergist with anti-PD-1.…”

Mitogen-Activated Protein Kinase and Nuclear Hormone Receptor Crosstalk in Cancer Immunotherapy

“…Lucitanib, a multi-kinase inhibitor, increased CD8+CD4+ T-cell counts and decreased the numbers of DCs and MDSCs in syngeneic mouse colon cancer models [60]. In combination with blocking Abs against inhibitory (PD1, CTLA4) and agonists against activatory (GITR, 4-1BB, ICOS, OX40) immune checkpoints, the anti-tumor response was potentiated.…”