Anti-angiogenesis for cancer revisited: Is there a role for combinations with immunotherapy?
Anti-angiogenesis for cancer revisited: Is there a role for combinations with immunotherapy?
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DOI：
10.1007/s10456-017-9552-y
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发表时间：
2017-05
期刊：
影响因子：
9.8
通讯作者：
Duda DG
中科院分区：
文献类型：
--
作者：
Ramjiawan RR;Griffioen AW;Duda DG
血管生成被定义为从预先存在的血管形成新的血管，并且已经被表征为肿瘤细胞增殖和存活的必要过程。这导致了用于抗血管生成的药理学试剂的发展，以破坏血管供应并使肿瘤缺乏营养和氧气，主要是通过阻断VEGF/VEGFR信号传导。这一努力已经导致11种抗VEGF药物被批准用于某些晚期癌症，单独或与化疗或其他靶向治疗联合使用。但这一成功对癌症患者的总体生存率影响有限，而且很少产生持久的反应。鉴于最近免疫疗法的成功，抗血管生成药物与免疫检查点阻断剂的组合已成为一种有吸引力的策略。然而，实现这样的组合将需要更好地理解其相互作用的机制。由于促血管生成因子在肿瘤中的过度表达，它们的血管系统通常是曲折和紊乱的，具有过度分支的渗漏血管。这增强了血管渗透性，这反过来又与高间质液压力以及血液灌注和氧合的减少有关。抗血管生成治疗的合理剂量可以通过降低血管通透性和改善肿瘤灌注和血流来使肿瘤血管系统暂时正常化，并在该时间窗内与免疫治疗协同作用。然而，抗血管生成药物可能以剂量和时间依赖性方式过度修剪肿瘤血管，这会诱导缺氧和免疫抑制，包括免疫检查点程序性死亡受体配体（PD-L1）的表达增加。本文综述了抗血管生成与免疫治疗相结合作为癌症治疗策略的概念。
Angiogenesis is defined as the formation of new blood vessels from pre-existing vessels, and has been characterized as an essential process for tumor cell proliferation and viability. This has led to the development of pharmacological agents for anti-angiogenesis to disrupt the vascular supply and starve tumor of nutrients and oxygen, primarily through blockade of VEGF/VEGFR signaling. This effort has resulted in 11 anti-VEGF drugs approved for certain advanced cancers, alone or in combination with chemotherapy or other targeted therapies. But this success had only limited impact on overall survival of cancer patients, and rarely resulted in durable responses. Given the recent success of immunotherapies, combinations of anti-angiogenics with immune checkpoint blockers have become an attractive strategy. However, implementing such combinations will require a better mechanistic understanding of their interaction. Due to overexpression of pro-angiogenic factors in tumors, their vasculature is often tortuous and disorganized, with excessively branched leaky vessels. This enhances vascular permeability, which in turn is associated with high interstitial fluid pressure, and a reduction in blood perfusion and oxygenation. Judicious dosing of anti-angiogenic treatment can transiently normalize the tumor vasculature by decreasing vascular permeability and improving tumor perfusion and blood flow, and synergize with immunotherapy in this time-window. However, anti-angiogenics may excessively prune tumor vessels in a dose and time-dependent manner, which induces hypoxia and immunosuppression, including increased expression of the immune checkpoint programmed death receptor ligand (PD-L1). This review focuses on revisiting the concept of anti-angiogenesis in combination with immunotherapy as a strategy for cancer treatment.