Combinational Immunotherapy Targeting the Melanoma-Associated Vasculature

描述（由申请人提供）：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名患者确诊，8，700人死亡。尽管最近BRAF抑制剂和伊匹单抗（抗CTLA-4 mAb）在黑色素瘤患者中提供客观临床应答方面取得了成功，但这些益处通常持续时间较短，仅在5-15%的治疗个体中观察到持久应答。疾病复发和治疗难治性疾病的发展的主要原因反映了给定病变中肿瘤细胞的遗传异质性和肿瘤细胞亚群的能力， 选择补偿性生长和生存途径，绕过特定的治疗封锁。作为绕过这种肿瘤内在限制的尝试，我们最近开发了促进CD 8 + T细胞靶向肿瘤相关血管细胞而不是正常组织相关血管细胞的疫苗。在应用于HLA-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，基于酪氨酸激酶抑制剂如达沙替尼（DAS）的共同施用，基于这种drg减少免疫调节细胞、增加荷瘤宿主中疫苗诱导的T效应细胞的“脱靶”能力，并改变肿瘤微环境中的趋化因子和整联蛋白表达，以促进保护性CD 8 + T细胞的募集。基于这些初步研究结果，我们假设由基于肿瘤血管抗原的疫苗和达沙替尼组成的联合治疗将被证明是安全的，并且在患有晚期黑色素瘤的HLA-A2+患者中有效性增加（目标1）。鉴于我们在HLA-A2 Tg小鼠亚组中发现了休眠的、隐匿的黑色素瘤，这些小鼠已经用抗血管疫苗有效治疗，我们还将检验这样一种假设，即通过联合治疗，增强CD 8 + T细胞识别和调节黑色素瘤起始细胞，可以提高这些动物的完全“分子治愈”率。（又称黑色素瘤干细胞或自我更新黑色素瘤细胞）或在体内阻断肿瘤（促存活）自噬途径（Aim 2）。基于我们的临床前建模，我们相信这些研究的成功完成将为有效治疗广泛的实体（血管化）癌症定义一种新的治疗模式。

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.