Bevacizumab plus Ipilimumab in Unresectable Stage III or Stage IV Melanoma

描述（由申请方提供）：针对共刺激分子细胞毒性T淋巴细胞抗原-4（CTLA-4）的全人源单克隆抗体的临床研究已证明对转移性黑色素瘤患者亚组具有持久获益。这些临床研究还为有效的抗肿瘤免疫应答机制提供了重要的见解，为癌症治疗提供了新的机会。我们已经发现，用伊匹单抗阻断CTLA-4可以在治疗后活检中诱导对供给肿瘤沉积物的脉管系统的深刻免疫介导的破坏。虽然这强调了血管生成对肿瘤生长的至关重要性，但它也推断了免疫系统以选择性方式识别并有效破坏肿瘤血管系统的能力。靶向血管内皮生长因子（VEGF）的临床功效及其对肿瘤血管生成的作用已经在使用抗VEGF抗体贝伐单抗的临床试验中被广泛研究。VEGF对抗原呈递细胞也具有强的免疫抑制功能。因此，当将VEGF的靶向与通过CTLA-4阻断的免疫调节组合时，存在对肿瘤脉管系统的潜在协同作用。鉴于我们观察到接受伊匹单抗治疗的黑色素瘤患者对肿瘤血管系统的深远影响以及贝伐单抗的已知影响，我们提出了一项I期研究，在转移性黑色素瘤患者中测试这些药物的组合。 公共卫生相关性：最近，对免疫功能机制的进一步理解提供了新的方法来解除免疫系统的制动以治疗癌症。一种这样的方法是阻断分子细胞毒性T淋巴细胞抗原-4（CTLA-4），这是免疫系统的先天抑制信号。在患者中阻断CTLA-4的初步证据表明，这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对滋养肿瘤的血管的免疫攻击。此外，已知参与滋养肿瘤的血管形成的主要因子血管内皮生长因子（VEGF）也被发现抑制免疫系统。一种阻断VEGF的抗体已被证明在与其他治疗方法（如化疗）联合使用时对许多类型的癌症非常有效。我们建议首次将阻断CTLA-4的抗体与阻断VEGF的抗体联合收割机结合，以阻断肿瘤血管形成。重要的是，我们试图了解这两种药物联合使用的协同作用，这两种药物可以靶向供应黑色素瘤沉积物的血管。

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.