SPORE in Skin Cancer

项目摘要--总体 这个Wistar/UPenn皮肤孢子代表了一项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的治疗方法，以至于每个高危黑色素瘤患者 会在某一时刻接受这些药物的治疗。然而，许多主要问题仍然是如何最好地使用 这些免疫疗法。项目1将解决未得到满足的需求，即寻找有效的生物标记物进行选择 患者接受单剂免疫治疗与联合免疫治疗。许多患者开始使用ipilimumab治疗， Nivolumab，当他们可能只对抗PD-1抗体(Ab)有反应时，暴露于这些患者 不必要地增加联合检查点抑制的毒性。项目1建立在一个基本发现的基础上 通过我们的开发研究计划(DRP)得出的结论是，胞外体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效用研究，以证明这种血液- 基础检测作为抗PD-1抗体(Ab)基础的高度敏感和特异的预测生物标志物 心理治疗。项目2将解决第二个未得到满足的需求，即更安全和有效的联合方案，承诺 对抗PD-1抗体难治性患者有效。基于大量的临床前数据和一种新的分子 针对自噬途径，我们开展了联合抗PD1抗体和自噬的临床试验 抑制：一种重新编程肿瘤相关巨噬细胞以增强T细胞效能的新策略 杀戮。项目3通过使用抗PD1抗体进行临床试验，填补了早期疾病治疗方面的一个主要空白 在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，以增强树突状细胞的免疫刺激能力 肿瘤微环境。这三个高度翻译的项目得到了长期核心的支持，这些核心 在适应快速变化的黑色素瘤和非黑色素瘤皮肤需求方面有良好的记录 癌症研究人员。每一个项目都是由现任孢子领导层根据其潜在的重要意义而选择的， 影响和创新。它们结合在一起，有可能推进可用于治疗的生物学见解。 黑色素瘤患者的新的、临床上重要的治疗方法。来自孢子的资金为我们提供了 具有重要的优势，包括成熟的、集体的、翻译的心态，有效运作的肿瘤 银行，以及维斯塔尔研究所和宾夕法尼亚大学之间高度演变的合作框架。孢子 使我们能够在整个过程中加强与学术和行业合作伙伴的横向和纵向合作 整个世界。职业提升计划和DRP使过渡到新的领导层成为可能，已经形成 这三个项目被提出，并使我们的研究能够触及其他皮肤癌，包括 SCC、CTCL和Merkel细胞癌。这些项目将继续得到Strong公司的大力支持 来自维斯塔尔大学和宾夕法尼亚大学的机构支持。对这个孢子的资助将带来新的进展 长凳到床边，完成我们提高皮肤癌患者存活率的总体使命。

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.