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

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。已经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IFNα-2b在转移性黑色素瘤患者中的疗效的假设。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介导的抗增殖和促凋亡活性的敏感性; 2）通过上调肿瘤抗原呈递和下调T细胞介导的免疫应答来增加对黑色素瘤细胞的免疫应答。 抑制性受体配体; 3）抑制荷黑色素瘤小鼠的存活。这些发现反映了BRAFi治疗后携带BRAF突变的黑色素瘤细胞的IFNα-2b敏感性增加。为了评估我们的实验数据的临床意义，提出的特定目的将检验以下假设：1）BRAFi和IFNα-2b对转移性黑色素瘤患者的给药是安全的、无毒的和免疫原性的; 2）BRAFi的施用增强了IFNα-γ的抗增殖和促凋亡活性。2b以及其上调黑素瘤细胞表达HLA I类APM组分的表达的能力; 3）BRAFi和IFNα-2b的施用增加了肿瘤微环境中的肿瘤抗原（TA）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组合的治疗相关性及其治疗作用的分子机制。

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.