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

维莫非尼和高剂量干扰素 Alpha-2b 对于晚期患者的安全性和有效性

• 批准号: 8554637
• 负责人: SOLDANO FERRONE
• 金额: $ 28.8万
• 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/8554637
• 关键词: Adjuvant; Airborne Particulate Matter; Antigen Presentation; Antigens; BRAF gene; Cell surface; Cells; Clinical; Data; Disease Progression; Dose; Down-Regulation; Experimental Models; HLA Antigens; In Vitro; Interferons; Ligands; MAP Kinase Gene; Mediating; Melanoma Cell; Metastatic Melanoma; Molecular; Mus; Mutation; 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 IFN¿-2b in patients with metastatic melanoma. This hypothesis stems from our novel findings that BRAFi: 1) enhances the sensitivity of melanoma cells to IFN-¿-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 IFN¿-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 IFN¿-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 IFN¿-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 IFN¿-2b increases tumor antigen (TA)-specific T cell expansion and function in the tumor microenvironment. The information derived from the outlined studies will contribute to determine the therapeutic relevance of the BRAFi/IFN¿-2b combination and the molecular mechanisms underlying its therapeutic effects.

临床证据令人信服地表明，BRAF抑制剂（BRAFi）如维罗非尼在>50%携带V600 E BRAF突变的转移性黑色素瘤患者中诱导客观肿瘤消退。然而，肿瘤消退很少是完全的，并且疾病进展发生在治疗的中位时间6-7个月。已发现多种机制支持黑素瘤细胞对BRAFi的内在和获得性抗性，并且代表了在患有晚期黑素瘤的患者中使用BRAFi作为单一药剂的主要限制。因此，现在关键的是定义根除BRAFi敏感性和抗性黑素瘤细胞的组合策略。在本提案中，我们将检验BRAFi（vemurafenib）增强IFN <$-2b在转移性黑色素瘤患者中的治疗效果的假设。这一假设源于我们的新发现，即BRAFi：1）增强黑色素瘤细胞对IFN-γ介导的抗增殖和促凋亡活性的敏感性; 2）通过上调肿瘤抗原呈递和下调黑色素瘤细胞抑制性受体配体的表达来增加T细胞介导的对黑色素瘤细胞的免疫应答; 3）延长荷黑色素瘤小鼠的存活。这些发现反映了在用BRAFi治疗后，携带BRAF突变的黑素瘤细胞的IFN γ-2b敏感性增加。为了评估我们实验数据的临床意义，拟议的特定目标将测试以下假设：1）向转移性黑色素瘤患者给予BRAFi和IFNú-2b是安全、无毒且具有免疫原性的; 2）给予BRAFi增强抗增殖和促细胞凋亡活性干扰素的活性BRAFi和IFN-2b的施用增加了肿瘤微环境中肿瘤抗原（TA）特异性T细胞的扩增和功能。从概述的研究中获得的信息将有助于确定BRAFi/IFN <$-2b组合的治疗相关性及其治疗作用的分子机制。