SPORE in Skin Cancer

皮肤癌中的孢子

• 批准号: 10480828
• 负责人: RAVI K AMARAVADI
• 金额: $ 219.42万
• 依托单位: WISTAR INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-03 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10480828
• 关键词: Address; Adjuvant; Antibody Therapy; Autophagocytosis; BRAF gene; Biological; Biological Assay; Biological Markers; Blood; CD8-Positive T-Lymphocytes; Cancer Patient; Clinical; Clinical Investigator; Clinical Management; Clinical Trials; Collaborations; Combination immunotherapy; Cutaneous Melanoma; Cutaneous T-cell lymphoma; Data; Death Rate; Dendritic Cells; Development; Disease; Disease Progression; Disease regression; Dose; Drug Design; Early treatment; Funding; Genetic; Genomics; Immune; Immune checkpoint inhibitor; Immune response; Immunologics; Immunotherapeutic agent; Immunotherapy; Impairment; In complete remission; Institution; Intervention Trial; Knowledge; Leadership; Life; Lymphoma cell; Malignant Neoplasms; Measurement; Medicine; Mentors; Merkel cell carcinoma; Mission; Molecular Target; Nature; Neoadjuvant Therapy; Nivolumab; Operative Surgical Procedures; Pathologic; Pathway interactions; Patients; Peripheral; Recording of previous events; Refractory; Regimen; Reporting; Research; Research Design; Research Personnel; Resources; Scientist; Sensitivity and Specificity; Series; Skin; Skin Cancer; Skin Carcinoma; T-Lymphocyte; The Wistar Institute; Therapeutic; Toxic effect; Translating; Treatment-related toxicity; Tumor Bank; Tumor-associated macrophages; Work; anti-PD1 antibodies; anti-PD1 therapy; base; bench to bedside; career; cell killing; checkpoint inhibition; cohort; design; disorder risk; effective therapy; exosome; experience; high risk; improved; industry partner; inhibition of autophagy; inhibitor; innovation; insight; ipilimumab; macrophage; melanoma; mutant; neoplastic cell; novel; novel drug combination; novel strategies; novel therapeutic intervention; pembrolizumab; pre-clinical; preclinical study; predicting response; predictive marker; programmed cell death ligand 1; programs; response; response biomarker; side effect; skin squamous cell carcinoma; targeted treatment; treatment response; tumor microenvironment; tumor progression; tumorigenic

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.

项目摘要 - 总体 这款Wistar/Upenn Skin Spore代表了非常成功且长期的合作。免疫 检查点抑制已彻底改变了黑色素瘤疗法 这些代理商将在某个时候对待。但是，关于如何最好地使用的许多主要问题仍然存在 这些免疫治疗。项目1将解决找到有效的生物标志物选择的未满足的需求 单药与组合免疫疗法的患者。许多患者开始使用ipilimumab和 nivolumab，当它们可能仅对抗PD-1抗体（AB）反应时，暴露了这些患者 组合检查点抑制的毒性不必要。项目1建立在基本发现的基础上 通过我们的发展研究计划（DRP），外泌体PD-L1是一种免疫抑制 黑色素瘤分泌的因素。我们提出了严格的临床公用事业研究，旨在证明这种血液 基于抗PD-1抗体（AB）的高度敏感和特异性的预测生物标志物基于高度敏感和特定的预测生物标志物（AB） 治疗。项目2将解决对承诺更安全，有效的组合方案的第二个未满足的需求 对抗PD-1 AB难治性患者有效。基于广泛的临床前数据和新的分子 在自噬途径中的目标，我们已经开发了一项抗PD1 AB和自噬的临床试验 抑制作用，一种重新编程肿瘤相关巨噬细胞以提高T细胞效率的新策略 杀人。项目3通过使用抗PD1 AB进行临床试验，填补了早期疾病治疗的主要空白 在IIB/C期黑色素瘤患者中。除了对免疫反应的深入表征，该项目的 临床前研究将导致增强树突状细胞免疫刺激能力的新策略 肿瘤微环境。这三个高度翻译的项目得到了长期存在的核心的支持 具有适应黑色素瘤和非黑色素瘤皮肤的快速变化需求的可靠记录 癌症研究人员。每个项目都是由当前的孢子领导选择其重要性的， 影响与创新。他们在一起有可能提高历史可利用的生物学见解 进入黑色素瘤患者的新型，临床上重要的疗法。孢子的资金为我们提供了 具有重要的优势，包括成熟，集体，翻译的思维定势，有效的功能肿瘤 银行，以及Wistar Institute和Upenn之间的高度发展的合作框架。孢子 允许我们在整个过程中与学术和行业合作伙伴建立水平和垂直合作 世界。职业增强计划和DRP已使过渡到新领导，已经形成了 提出了这三个项目，并允许我们的研究进入皮肤的其他癌症，包括 SCC，CTCL和默克尔细胞癌。这些计划将继续得到强大的支持 Wistar和Upenn的机构支持。该孢子的资金将带来新的进步 长凳到床边，并履行我们改善皮肤癌患者生存的整体任务。