Targeting Tumor Angiogenesis with the Selective VEGFR-3 Inhibitor EVT801 in Combination with Cancer Immunotherapy

Area of Science:

• Oncology
• Molecular Biology
• Immunology

Background:

• Vascular Endothelial Growth Factor Receptor 3 (VEGFR-3) is a key driver of tumor angiogenesis and lymphangiogenesis, crucial for tumor growth and metastasis.
• Existing VEGFR inhibitors like sorafenib and pazopanib have limitations in selectivity and toxicity.
• Targeting VEGFR-3 offers a potential strategy to inhibit tumor progression and enhance anti-cancer therapies.

Purpose of the Study:

• To introduce and characterize a novel, selective VEGFR-3 inhibitor, EVT801.
• To evaluate the efficacy of EVT801 as a monotherapy and in combination with immune checkpoint therapy (ICT) in preclinical cancer models.
• To investigate the mechanisms underlying EVT801's antitumor effects, including its impact on tumor microenvironment and immunosuppression.

Main Methods:

• In vitro assessment of EVT801's effect on endothelial cell proliferation.
• In vivo studies using VEGFR-3 positive tumor mouse models to evaluate antitumor activity, tumor hypoxia, and blood vessel normalization.
• Analysis of immunosuppressive cytokines (CCL4, CCL5) and myeloid-derived suppressor cells (MDSCs) in circulation.
• Combination therapy studies with EVT801 and ICT in carcinoma models.

Main Results:

• EVT801 demonstrated potent antitumor effects in VEGFR-3 positive tumors and microenvironments, with improved selectivity and reduced toxicity compared to existing inhibitors.
• EVT801 suppressed VEGF-C-induced endothelial cell proliferation and tumor (lymph)angiogenesis.
• Treatment with EVT801 led to reduced tumor hypoxia, normalized tumor vasculature, and decreased levels of immunosuppressive factors (CCL4, CCL5) and MDSCs.
• Combination of EVT801 with ICT resulted in superior antitumor outcomes compared to monotherapy, with tumor growth inhibition inversely correlated with CCL4, CCL5, and MDSC levels.

Conclusions:

• EVT801 is a highly selective VEGFR-3 inhibitor with potent antitumor activity and a favorable toxicity profile.
• EVT801 exerts its effects by normalizing tumor vasculature, reducing hypoxia, and mitigating immunosuppression.
• EVT801 holds significant promise as an anti(lymph)angiogenic agent for enhancing the efficacy of immune checkpoint inhibitors in patients with VEGFR-3 positive tumors.