Bevacizumab plus Ipilimumab in Unresectable Stage III or Stage IV Melanoma

描述(由申请人提供)：针对共刺激分子细胞毒性T淋巴细胞抗原-4(CTLA-4)的全人单抗的临床研究表明，对转移性黑色素瘤患者的亚群有持久的好处。这些临床研究还为有效的抗肿瘤免疫反应的机制提供了重要的见解，为癌症的治疗提供了新的机会。我们已经发现，用ipilimumab阻断CTLA-4可以诱导治疗后活检组织中供血肿瘤沉积的血管受到免疫介导的严重破坏。虽然这强调了血管生成对肿瘤生长的关键重要性，但它也推断了免疫系统有选择地识别和有效破坏肿瘤血管的能力。针对血管内皮生长因子(VEGF)的临床疗效及其对肿瘤血管生成的影响已在抗血管内皮生长因子抗体贝伐单抗的临床试验中得到广泛研究。血管内皮生长因子对抗原提呈细胞也有很强的免疫抑制作用。因此，当靶向血管内皮生长因子与通过阻断CTLA-4进行免疫调节相结合时，对肿瘤血管存在潜在的协同作用。鉴于我们观察到接受ipilimumab治疗的黑色素瘤患者对肿瘤血管的深刻影响以及贝伐单抗的已知作用，我们建议进行一项I期研究，测试这些药物在转移性黑色素瘤患者中的组合。 与公共卫生相关：最近，对免疫功能机制的了解的提高提供了新的方法来解除免疫系统的刹车，以治疗癌症。其中一种方法是阻断细胞毒性T淋巴细胞抗原-4(CTLA-4)分子，CTLA-4是免疫系统的一种天生抑制信号。初步证据表明，在患者中阻断CTLA-4可以有效地治疗黑色素瘤。有趣的是，抗肿瘤反应的一部分涉及为肿瘤提供血液的血管的免疫攻击。此外，已知的与肿瘤血管形成有关的主要因素--血管内皮生长因子(VEGF)--也被发现抑制免疫系统。一种阻断血管内皮生长因子的抗体已被证明与其他治疗方法(如针对多种癌症的化疗)联合使用时非常有效。我们建议首次将阻断CTLA-4的抗体与阻断血管内皮生长因子的抗体结合起来，以阻止肿瘤的血管形成。重要的是，我们试图了解这两种药物联合使用时的协同效应，这两种药物一起可以靶向供应黑色素瘤沉积的血管。

DESCRIPTION (provided by applicant): The clinical investigation of fully human monoclonal antibodies against the costimulatory molecule Cytotoxic T-Lymphocyte Antigen-4 (CTLA-4) has demonstrated durable benefit for a subset of patients with metastatic melanoma. These clinical investigations have also provided important insight into mechanisms of effective anti-tumor immune responses that have provided new opportunities for cancer treatments. We have discovered that CTLA-4 blockade with ipilimumab can induce profound immune mediated destruction of the vasculature feeding tumor deposits in post-treatment biopsies. While this emphasizes the critical importance of angiogenesis to tumor growth, it also infers an ability of the immune system to recognize and effectively destroy tumor vasculature in a selective manner. The clinical efficacy of targeting vascular endothelial growth factor (VEGF) and its effect on tumor angiogenesis has been extensively studied in clinical trials with the use of the anti-VEGF antibody bevacizumab. VEGF also possesses potent immune suppressive function on antigen presenting cells. As a result, potential synergic effects on the tumor vasculature exist when combining the targeting of VEGF with immune modulation through CTLA-4 blockade. Given our observations of the profound effects on tumor vasculature in melanoma patients receiving ipilimumab and the known effects of bevacizumab, we propose a phase I study testing the combination of these agents in patients with metastatic melanoma. PUBLIC HEALTH RELEVANCE: Improved understanding of mechanisms of immune function has recently provided novel ways to take the brakes off the immune system to treat cancer. One such means has been to block the molecule Cytotoxic T-Lymphocyte Antigen-4 (CTLA-4), an innate inhibitory signal to the immune system. Preliminary evidence for blocking CTLA-4 in patients has shown that this can be accomplished to effectively treat melanoma. Interestingly, part of the anti-tumor response involves an immune attack of the blood vessels feeding the tumors. In addition, the major factor known to be involved in the formation of blood vessels that feed tumors, vascular endothelial growth factor (VEGF), has also been found to suppress the immune system. An antibody that blocks VEGF has been shown to be highly effective when combined with other treatments such as chemotherapy against many types of cancer. We propose to combine for the first time an antibody that blocks CTLA-4 to take the brakes off the immune system with an antibody that blocks VEGF to block blood vessel formation to tumors. Importantly we seek to understand synergies in combining these two drugs that together could target the blood vessels feeding melanoma deposits.