Ipilimumab improves survival in advanced melanoma and can induce immune mediated tumor vasculopathy. Besides promoting angiogenesis, VEGF suppresses dendritic cell maturation and modulates lymphocyte endothelial trafficking. This study investigated the combination of CTLA-4 blockade with ipilimumab and VEGF inhibition with bevacizumab. Patients with metastatic melanoma were treated in four dosing cohorts of ipilimumab (3 or 10 mg/kg) every 3 weeks for four doses then every 12 weeks, and bevacizumab (7.5 or 15 mg/kg) every 3 weeks. Forty-six patients were treated. Inflammatory events included giant cell arteritis(1), hepatitis(2), and uveitis(2). On-treatment tumor biopsies revealed activated vessel endothelium with extensive CD8+ and macrophage cell infiltration. Peripheral blood analyses demonstrated increases in CCR7+/-/CD45RO+ cells and anti-galectin antibodies. Best overall response included 8 partial responses, 22 stable disease, and disease-control rate (DCR) 67.4%. Median survival was 25.1 months. Bevacizumab influences changes in tumor vasculature and immune responses with ipilimumab administration.The combination of bevacizumab and ipilimumab can be safely administered and reveals VEGF-A blockade influences on inflammation, lymphocyte trafficking, and immune regulation. This provides a basis for further investigating the dual roles of angiogenic factors in blood vessel formation and immune regulation as well as future combinations of anti-angiogenesis agents and immune checkpoint blockade.
- Received March 26, 2014.
- Revision received March 28, 2014.
- Accepted April 7, 2014.
- Copyright © 2014, American Association for Cancer Research.