Combinational Immunotherapy Targeting the Melanoma-Associated Vasculature

描述(申请人提供)：黑色素瘤的发病率继续以惊人的速度上升，2011年估计有70,000名患者被诊断为黑色素瘤，8,700人死于这种疾病。尽管最近BRAF抑制剂和ipilumimab(抗CTLA-4单抗)在为黑色素瘤患者提供客观的临床反应方面取得了成功，但这种益处通常持续时间较短，仅有5%-15%的接受治疗的患者观察到持久的反应。疾病复发和难治性疾病发展的一个主要原因反映了特定病变中肿瘤细胞的遗传异质性以及肿瘤细胞亚群的能力 选择可绕过特定治疗障碍的补偿性生长和生存途径。为了试图绕过这种肿瘤固有的限制，我们最近开发了促进CD8+T细胞靶向肿瘤相关血管细胞的疫苗，而不是正常组织相关的血管细胞。在应用于人类白细胞抗原A2转基因(TG)小鼠的黑色素瘤模型中，这些疫苗可以促进肿瘤消退和持久的无病状态。我们还确定，治疗性疫苗可能会变得越来越有效，基础是联合应用酪氨酸激酶抑制剂，如达沙替尼(DAS)，基于这种DRG的“非靶点”能力，减少免疫调节细胞，增加疫苗诱导的肿瘤宿主中的T效应细胞，并改变肿瘤微环境中趋化因子和整合素的表达，以促进保护性CD8+T细胞的招募。基于这些初步发现，我们假设，由肿瘤血管抗原疫苗和达沙替尼组成的联合疗法将被证明是安全的，并且在人类白细胞抗原A2+晚期黑色素瘤患者中具有更高的有效性(目标1)。鉴于我们在已用抗血管疫苗有效治疗的HL A-A2 TG小鼠中发现了潜伏性、隐匿性黑色素瘤的亚群，我们还将测试以下假设，即通过允许增强CD8+T细胞识别和调节黑色素瘤起始细胞(又名黑色素瘤干细胞或自我更新黑色素瘤细胞)或阻断肿瘤(有利于生存的)体内自噬途径的联合疗法，这些动物的完全“分子治愈”率可能会得到提高(目标2)。基于我们的临床前模型，我们相信，这些研究的成功完成将定义一种新的治疗模式，用于有效治疗广泛的实体(血管)癌症。

DESCRIPTION (provided by applicant): The incidence of melanoma continues to rise at an alarming pace, with estimates of the 70,000 patients diagnosed and 8,700 deaths attributable to this disease in 2011. Despite recent successes for BRAF inhibitors and ipilumimab (anti-CTLA-4 mAb) in providing objective clinical responses in melanoma patients, such benefits are typically of short duration, with durable responses observed in only 5-15% of treated individuals. A major reason for disease recurrence and the development of treatment-refractory disease reflects the genetic heterogeneity of tumor cells in a given lesion and the ability of subsets of tumor cells to select for compensatory growth and survival pathways that circumvent specific therapeutic blockade. As an attempt to bypass such tumor-intrinsic limitations, we have recently developed vaccines that promote CD8+ T cell targeting of tumor-, but not normal tissue-, associated blood vessel cells. In melanoma models applied to HLA-A2 transgenic (Tg) mice, these vaccines can promote tumor regression and durable disease-free status. We have also determined that therapeutic vaccines may become increasingly efficacious based on the co-administration of tyrosine kinase inhibitors, such as dasatinib (DAS), based on the "off target" abilities of this drg to diminish immune regulatory cells, to increase vaccine-induced T effector cells in the tumor-bearing host, and to alter chemokine and integrin expression in the tumor microenvironment to facilitate the recruitment of protective CD8+ T cells. Based on these preliminary findings, we hypothesize that combination therapies consisting of tumor blood vessel antigen-based vaccines and dasatinib will prove safe and of increased effectiveness in the setting of HLA-A2+ patients with advanced stage melanoma (Aim 1). Given our findings of dormant, occult melanomas in a subset of HLA-A2 Tg mice that have been effectively treated with anti-vascular vaccines, we will also test the hypothesis that the rate of complete "molecular cures" in these animals may be improved by combination therapies that allow for enhanced CD8+ T cell recognition and regulation of melanoma initiating cells (aka melanoma stem cells or self-renewing melanoma cells) or that block the tumor (pro-survival) autophagy pathway in vivo (Aim 2). Based on our pre-clinical modeling, we believe that the successful completion of these studies will define a novel therapeutic paradigm for the effective treatment of a broad range of solid (vascularized) cancers.