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

临床证据令人信服地表明，BRAF抑制剂（BRAFi）如vemurafenib可诱导50%的携带V600E BRAF突变的转移性黑色素瘤患者客观肿瘤消退。然而，肿瘤消退很少完全，并且在治疗的中位数为6-7个月时发生疾病进展。已经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，这是晚期黑色素瘤患者使用BRAFi作为单一药物的主要限制。因此，现在至关重要的是确定联合策略来根除BRAFi敏感和耐药的黑色素瘤细胞。在本提案中，我们将验证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-介导的抗增殖和促凋亡活性的敏感性；2)通过上调黑色素瘤细胞的肿瘤抗原呈递和下调抑制受体配体的表达，增加T细胞介导的对黑色素瘤细胞的免疫应答；3)延长黑色素瘤小鼠的生存期。这些发现反映了BRAF突变的黑色素瘤细胞在接受BRAFi治疗后，IFN¿-2b敏感性增加。为了评估我们的实验数据的临床意义，提出的特异性目标将检验以下假设：1)BRAFi和IFN¿-2b对转移性黑色素瘤患者是安全、无毒和免疫原性的；2) BRAFi可增强IFN¿-2b的抗增殖和促凋亡活性，上调黑色素瘤细胞HLA I类APM成分的表达；3) BRAFi和IFN¿-2b可增加肿瘤抗原（TA）特异性T细胞在肿瘤微环境中的扩增和功能。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 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.