SPORE in Skin Cancer

项目概要-总体 这个Wistar/UPenn皮肤孢子代表了一个非常成功和长期的合作。免疫 检查点抑制已经彻底改变了黑色素瘤治疗， 会在某个时候被这些药剂治疗然而，在如何最好地利用 这些免疫疗法。项目1将解决未满足的需求，以找到一种有效的生物标志物进行选择 单药与联合免疫治疗的患者。许多患者开始用易普利姆玛治疗， 纳武利尤单抗，当他们可能对单独的抗PD-1抗体（Ab）有反应时，暴露这些患者 不必要的联合检查点抑制的毒性。项目1建立在一个基本的发现之上 通过我们的发育研究计划（DRP），外泌体PD-L1是一种免疫抑制剂， 黑色素瘤分泌的因子。我们建议进行严格的临床应用研究来证明这种血液- 作为基于抗PD-1抗体（Ab）的高灵敏度和特异性预测生物标志物， 疗法项目2将解决第二个未满足的需求，即更安全有效的联合治疗方案， 在抗PD-1抗体难治性患者中有效。基于广泛的临床前数据和一种新的分子 针对自噬通路中的靶点，我们开发了一项联合抗PD 1抗体和自噬的临床试验， 抑制，重编程肿瘤相关巨噬细胞以增强T细胞功效的新策略 杀人项目3通过开展抗PD 1抗体临床试验填补了早期疾病治疗的重大空白 IIB/C期黑色素瘤患者。除了深入描述免疫反应，该项目的 临床前研究将导致新的策略，用于增强树突状细胞的免疫刺激能力， 肿瘤微环境这三个高度转化的项目得到了长期核心的支持， 在适应黑色素瘤和非黑色素瘤皮肤快速变化的需求方面有着良好的记录 癌症研究者每个项目都是由当前的SPORE领导层根据其潜在的重要性选择的， 影响和创新。总之，它们有可能推进可用于治疗的生物学见解 用于治疗黑色素瘤患者的新的、临床上重要的疗法。来自SPORE的资金为我们提供了 具有重要的优势，包括成熟，集体，转化的心态，有效运作的肿瘤， 银行，以及Wistar研究所和宾夕法尼亚大学之间高度发展的合作框架。孢子 使我们能够加强与学术和行业合作伙伴的横向和纵向合作， 世界职业提升计划和DRP已经实现了向新领导层的过渡， 这三个项目的提出，并使我们的研究达到其他癌症的皮肤，包括 SCC、CTCL和默克尔细胞癌。这些计划将继续得到强有力的支持， 来自Wistar和UPenn的机构支持。这一SPORE的资金将带来新的进步， 坐在床边，完成我们提高皮肤癌患者生存率的总体使命。

Project Summary – Overall This Wistar/UPenn Skin SPORE represents a highly successful and longstanding collaboration. Immune checkpoint inhibition has revolutionized melanoma therapy to the point where every high-risk melanoma patient will be treated at some point with these agents. However, many major questions remain on how best to use these immune therapeutics. Project 1 will address the unmet need to find an effective biomarker to select patients for single agent versus combination immunotherapy. Many patients start treatment with ipilimumab and nivolumab, when they may have responded to anti-PD-1 antibody (Ab) alone, exposing these patients unnecessarily to the toxicity of combination checkpoint inhibition. Project 1 builds on a fundamental discovery made through our Developmental Research Program (DRP) that exosomal PD-L1 is an immunosuppressive factor secreted by melanomas. We propose rigorous clinical utility studies designed to demonstrate this blood- based measurement as a highly sensitive and specific predictive biomarker for anti-PD-1 antibody (Ab)-based therapy. Project 2 will address a second unmet need for a safer and effective combination regimen that promises to be effective in anti-PD-1 Ab refractory patients. Based on extensive preclinical data and a new molecular target in the autophagy pathway, we have developed a clinical trial of combined anti-PD1 Ab and autophagy inhibition, a new strategy for reprogramming tumor-associated macrophages to enhance the efficacy of T cell killing. Project 3 fills a major gap in the treatment of early disease by conducting a clinical trial with anti-PD1 Ab in Stage IIB/C melanoma patients. Besides in-depth characterization of the immune response, the Project’s preclinical studies will lead to new strategies for enhancing the immune stimulatory capacity of dendritic cells in the tumor microenvironment. These three highly translational Projects are supported by longstanding Cores that have a proven track record of adapting to the rapidly changing needs of melanoma and non-melanoma skin cancer researchers. Each Project was chosen by the current SPORE leadership for its potential for significance, impact and innovation. Together, they have the potential to advance therapeutically exploitable biological insights into new, clinically important therapies of patients with melanoma. Funding from the SPORE has provided us with important advantages, including a mature, collective, translational mindset, an efficiently functioning tumor bank, and a highly evolved framework of collaboration between The Wistar Institute and UPenn. The SPORE has allowed us to bolster horizontal and vertical collaborations with academic and industry partners throughout the world. The Career Enhancement Program and DRP have enabled transition to new leadership, have formed the three Projects proposed, and have allowed our research to reach into other cancers of the skin including SCC, CTCL and Merkel Cell carcinoma. These programs will continue to be supported robustly by strong institutional support from both Wistar and UPenn. Funding of this SPORE will bring new advances from the bench to the bedside and fulfill our overall mission of improving survival for skin cancer patients.