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

临床证据令人信服地表明，像Vemurafenib这样的BRAF抑制剂(BRAFi)可以在携带V600E BRAF突变的转移性黑色素瘤患者中诱导客观的肿瘤消退。然而，肿瘤的消退很少是完全的，疾病进展发生在治疗的中位数6-7个月。多种机制(S)已被发现支持黑色素瘤细胞对BRAFi的内在和获得性耐药性，并代表着BRAFi作为单一药物用于晚期黑色素瘤患者的主要限制。因此，现在至关重要的是确定组合策略来根除BRAFi敏感和耐药的黑色素瘤细胞。在这项提案中，我们将检验BRAFI(维莫拉非尼)增强干扰素α-2b对转移性黑色素瘤患者的治疗效果的假设。这一假说源于我们的新发现：1)提高了黑色素瘤细胞对干扰素α介导的抗增殖和促凋亡活性的敏感性；2)通过上调肿瘤抗原提呈和下调T细胞对黑色素瘤细胞的表达，增强了T细胞介导的免疫应答。 黑色素瘤细胞的抑制性受体配体和；3)延长黑色素瘤荷瘤小鼠的存活时间。这些发现反映了携带BRAF突变的黑色素瘤细胞在接受BRAFI治疗后对干扰素α-2b的敏感性增加。为了评估我们实验数据的临床意义，拟议的特异性目标将检验以下假设：1)BRAFi和干扰素α-2b对转移性黑色素瘤患者是安全、无毒和具有免疫原性的；2)BRAFi和干扰素α-2b的应用增强了黑色素瘤细胞的抗增殖和促凋亡活性，以及其上调黑色素瘤细胞表达HLAI类APM成分的能力；3)BRAFi和干扰素α-2b的应用增加了肿瘤抗原(TA)特异性T细胞的增殖和在肿瘤微环境中的功能。从概述的研究中获得的信息将有助于确定BRAFI/干扰素α-2b组合的治疗相关性及其治疗效果的分子机制。

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.