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）的全人源单克隆抗体的临床研究表明，对转移性黑色素瘤的一部分患者有持久的益处。这些临床研究也为有效的抗肿瘤免疫反应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，在治疗后活检中，伊匹单抗阻断CTLA-4可以诱导免疫介导的肿瘤沉积物供血血管的深度破坏。虽然这强调了血管生成对肿瘤生长的关键重要性，但它也推断出免疫系统有能力以选择性的方式识别并有效地破坏肿瘤血管。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经在使用抗VEGF抗体贝伐单抗的临床试验中得到了广泛的研究。VEGF对抗原提呈细胞也具有很强的免疫抑制作用。因此，将靶向VEGF与CTLA-4阻断免疫调节相结合，对肿瘤血管存在潜在的协同作用。鉴于我们观察到接受伊匹单抗和贝伐单抗对黑色素瘤患者肿瘤血管系统的深刻影响，我们提出了一项I期研究，测试这些药物在转移性黑色素瘤患者中的联合应用。

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.