SPORE in Skin Cancer

项目总结 – 总体 Wistar/UPenn Skin SPORE 代表了一次非常成功且长期的合作。免疫 检查点抑制彻底改变了黑色素瘤治疗，每位高危黑色素瘤患者 将在某个时候用这些药物进行治疗。然而，关于如何最好地使用仍然存在许多主要问题。 这些免疫疗法。项目 1 将解决寻找有效生物标志物来选择的未满足需求 单一药物与联合免疫治疗的患者。许多患者开始使用易普利姆玛 (ipilimumab) 治疗 nivolumab，当他们可能仅对抗 PD-1 抗体 (Ab) 产生反应时，暴露了这些患者 联合检查点抑制的毒性不必要地增加。项目 1 建立在一项基本发现的基础上 通过我们的发展研究计划 (DRP)，外泌体 PD-L1 是一种免疫抑制剂 黑色素瘤分泌的因子。我们提出严格的临床效用研究，旨在证明这种血液- 基于测量作为基于抗 PD-1 抗体 (Ab) 的高度敏感和特异性预测生物标志物 治疗。项目 2 将解决第二个未满足的需求，即更安全、更有效的联合治疗方案，该方案有望 对抗 PD-1 抗体难治性患者有效。基于广泛的临床前数据和新的分子 自噬途径中的靶点，我们开发了抗PD1抗体和自噬联合的临床试验 抑制，一种重新编程肿瘤相关巨噬细胞以增强 T 细胞功效的新策略 杀戮。项目3通过抗PD1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。除了免疫反应的深入表征之外，该项目的 临床前研究将带来增强树突状细胞免疫刺激能力的新策略 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拥有良好的记录 癌症研究人员。每个项目均由现任 SPORE 领导层因其潜在的重要性而选择， 影响和创新。他们共同拥有推进可治疗的生物学见解的潜力 为黑色素瘤患者提供具有临床重要意义的新疗法。 SPORE 的资金为我们提供了 具有重要的优势，包括成熟的、集体的、转化的思维方式、有效运作的肿瘤 银行，以及威斯塔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 已实现向新领导层的过渡，并已形成 提出的三个项目使我们的研究能够扩展到其他皮肤癌，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 Wistar 和宾夕法尼亚大学的机构支持。 SPORE 的资助将带来新的进展 站在床边，履行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.