Safety and Efficacy of Vemurafenib and High-Dose InterferonAlpha-2b for Advanced Melanoma

维莫非尼和高剂量干扰素 Alpha-2b 治疗晚期黑色素瘤的安全性和有效性

• 批准号: 9091453
• 负责人: HASSANE M ZAROUR
• 金额: $ 25.92万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-26 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9091453
• 关键词: Adjuvant; Airborne Particulate Matter; Antigen Presentation; Antigens; BRAF gene; Cell surface; Cells; Clinical; Data; Disease Progression; Dose; Down-Regulation; HLA Antigens; In Vitro; Interferon Alfa-2b; Interferon-alpha; Interferons; Ligands; MAP Kinase Gene; Mediating; Melanoma Cell; Metastatic Melanoma; Modeling; Molecular; Mus; Mutation; PDCD1LG1 gene; Patients; Play; Resistance; Role; Safety; Signal Transduction; Skin Cancer; T-Lymphocyte; Testing; Therapeutic; Therapeutic Effect; Treatment Efficacy; Tumor Antigens; Ubiquitination; Up-Regulation; Ursidae Family; base; cell mediated immune response; clinically significant; combinatorial; design; immunogenic; inhibitor/antagonist; melanoma; novel; receptor; response; safety testing; stem; tumor; tumor microenvironment; type I interferon receptor; ubiquitin-protein ligase

Clinical evidence has convincingly shown that the BRAF inhibitors (BRAFi) like vemurafenib induce objective tumor regression in >50% of patients with metastatic melanoma that bear the V600E BRAF mutation. However, the tumor regressions are infrequently complete and disease progression occurs at a median of 6-7 months of treatment. Multiple mechanism(s) have been found to support the intrinsic and acquired resistance of melanoma cells to BRAFi and represent major limitations to the use of BRAFi as a single agent in patients with advanced melanoma. Therefore, it is now critical to define combinatorial strategies to eradicate BRAFi sensitive and resistant melanoma cells. In this proposal we will test the hypothesis that BRAFi (vemurafenib) enhances the therapeutic efficacy of IFNα-2b in patients with metastatic melanoma. This hypothesis stems from our novel findings that BRAFi: 1) enhances the sensitivity of melanoma cells to IFNα-mediated anti-proliferative and proapoptotic activity; 2) increases T cell-mediated immune responses to melanoma cells by upregulating tumor antigen presentation and downregulating the expression of inhibitory receptor ligand by melanoma cells and; 3) prolongs the survival of melanoma bearing mice. These findings reflect an increased IFNα-2b sensitivity of melanoma cells harboring BRAF mutations upon treatment with BRAFi. To assess the clinical significance of our experimental data, the proposed Specific Aims will test the following hypotheses: 1) The administration of BRAFi and IFNα-2b to patients with metastatic melanoma is safe, non toxic and immunogenic; 2) The administration of BRAFi enhances the antiproliferative and proapoptotic activity of the of IFNα-2b as well as its ability to upregulate the expression of HLA class I APM component expression by melanoma cells and; 3) The administration of BRAFi and IFNα-2b increases tumor antigen (TA)-specific T cell expansion and function in the tumor microenvironment. The information derived from the outlined studies will conthbute to determine the therapeutic relevance of the BRAFi/IFNα-2b combination and the molecular mechanisms underlying its therapeutic effects.

临床证据令人信服地表明，像维莫非尼这样的 BRAF 抑制剂 (BRAFi) 可以在超过 50% 的携带 V600E BRAF 突变的转移性黑色素瘤患者中诱导客观肿瘤消退，但肿瘤消退很少能完全实现，并且疾病进展的中位数为 100%。 6-7 个月的治疗已发现多种机制支持黑色素瘤细胞对 BRAFi 的内在和获得性耐药性，并代表了 BRAFi 使用的主要限制。因此，现在至关重要的是确定根除 BRAFi 敏感和耐药黑色素瘤细胞的组合策略。在本提案中，我们将检验 BRAFi（维莫非尼）增强 IFNα-2b 治疗效果的假设。这一假设源于我们的新发现，即 BRAFi：1) 增强黑色素瘤细胞对 IFNα 介导的抗增殖和抗肿瘤作用的敏感性。 2) 通过上调肿瘤抗原呈递和下调肿瘤抗原表达来增强 T 细胞介导的对黑色素瘤细胞的免疫反应。 黑色素瘤细胞的抑制性受体配体；3) 延长携带黑色素瘤的小鼠的存活时间。具体目标将测试以下假设：1）对转移性黑色素瘤患者施用 BRAFi 和 IFNα-2b 是安全、无毒且具有免疫原性的；2） BRAFi 增强 IFNα-2b 的抗增殖和促凋亡活性及其上调黑色素瘤细胞 HLA I 类 APM 成分表达的能力；3) BRAFi 和 IFNα-2b 的施用增加肿瘤抗原 (TA) -肿瘤微环境中的特异性 T 细胞扩增和功能从概述的研究中获得的信息将有助于确定 BRAFi/IFNα-2b 组合的治疗相关性和其治疗作用背后的分子机制。