Bevacizumab plus ipilimumab in patients with metastatic melanoma.
Bevacizumab plus ipilimumab in patients with metastatic melanoma.
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DOI：
10.1158/2326-6066.cir-14-0053
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发表时间：
2014-07
影响因子：
10.1
通讯作者：
McDermott D
中科院分区：
文献类型：
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作者：
Hodi FS;Lawrence D;Lezcano C;Wu X;Zhou J;Sasada T;Zeng W;Giobbie-Hurder A;Atkins MB;Ibrahim N;Friedlander P;Flaherty KT;Murphy GF;Rodig S;Velazquez EF;Mihm MC Jr;Russell S;DiPiro PJ;Yap JT;Ramaiya N;Van den Abbeele AD;Gargano M;McDermott D
伊匹木单抗可提高晚期黑色素瘤患者的生存率，并能诱导免疫介导的肿瘤血管病变。血管内皮生长因子（VEGF）除了促进血管生成外，还抑制树突状细胞成熟并调节淋巴细胞的内皮迁移。本研究探讨了CTLA - 4阻断剂伊匹木单抗与VEGF抑制剂贝伐珠单抗的联合应用。转移性黑色素瘤患者被分为四个剂量组，分别接受伊匹木单抗（3或10mg/kg）治疗，每3周给药一次，共4次，之后每12周给药一次，同时接受贝伐珠单抗（7.5或15mg/kg）治疗，每3周给药一次。共治疗了46例患者。炎症事件包括巨细胞动脉炎、肝炎和葡萄膜炎。治疗中的肿瘤活检显示活化的血管内皮伴有大量CD8 +和巨噬细胞浸润。外周血分析显示CCR7 +/−/CD45RO +细胞和抗半乳糖凝集素抗体增加。最佳总体反应包括8例部分缓解、22例病情稳定，疾病控制率（DCR）为67.4%。中位生存期为25.1个月。贝伐珠单抗影响伊匹木单抗给药时肿瘤血管和免疫反应的变化。贝伐珠单抗和伊匹木单抗联合应用是安全的，并且揭示了VEGF - A阻断对炎症、淋巴细胞迁移和免疫调节的影响。这为进一步研究血管生成因子在血管形成和免疫调节中的双重作用以及未来抗血管生成药物和免疫检查点阻断剂的联合应用提供了基础。
Ipilimumab improves survival in advanced melanoma and can induce immune-mediated tumor vasculopathy. Besides promoting angiogenesis, vascular endothelial growth factor (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) four doses at 3-week intervals and 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, hepatitis, and uveitis. 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 a disease-control rate (DCR) of 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.