Project 1: Hypoxia and metabolic dysregulation as a targetable barrier to immunotherapy in head and neck squamous cell carcinoma (HNSCC)

项目 1：缺氧和代谢失调作为头颈鳞状细胞癌 (HNSCC) 免疫治疗的目标障碍

• 批准号: 10704505
• 负责人: Greg M. Delgoffe
• 金额: $ 31.68万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10704505
• 关键词: Affect; Aftercare; American Society of Clinical Oncology; Animal Model; Automobile Driving; Award; Cell physiology; Cells; Clinical Research; Clinical Trials; Clinical Trials Design; Combination immunotherapy; Data; Development; Disease; Environment; Equilibrium; Exhibits; Functional disorder; Future; Goals; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Hypoxia; Image; Immune; Immune checkpoint inhibitor; Immune response; Immunity; Immunologics; Immunotherapy; Malignant Neoplasms; Metabolic; Metabolism; Metastatic/Recurrent; Metformin; Minority; Modeling; Nivolumab; Outcome; Oxidative Phosphorylation; Patients; Pharmaceutical Preparations; Phenotype; Phosphorylation Inhibition; Pre-Clinical Model; Productivity; Repression; Reproduction spores; Research; Research Personnel; Resistance; Sampling; Scanning; T-Lymphocyte; Testing; Therapeutic Clinical Trial; Tissues; Tumor Immunity; X-Ray Computed Tomography; anti-CTLA4; anti-PD-1; anti-PD1 therapy; cell type; checkpoint inhibition; clinical practice; combinatorial; design; immune cell infiltrate; immune checkpoint blockade; immunotherapy trials; improved; inhibitor; insight; ipilimumab; next generation; novel; novel therapeutics; patient population; pembrolizumab; personalized immunotherapy; pre-clinical; predicting response; programmed cell death protein 1; programs; radiomics; receptor; recruit; resistance mechanism; response; rosiglitazone; standard of care; targeted treatment; transcriptome sequencing; tumor; tumor hypoxia; tumor metabolism; tumor microenvironment

PROJECT SUMMARY − PROJECT 1 In recurrent and metastatic head and neck squamous cell carcinoma (R/M HNSCC), immune checkpoint blockade has changed the standard of care, with trials from HN SPORE PI Dr. Robert Ferris and co-I (Project 2) Dr. Barbara Burtness pioneering the use of anti-PD-1 in this setting. Unfortunately, only a minority of patients benefit, due to resistance to anti-PD-1 therapy, pointing to an urgent need to better understand the tumor microenvironment. With HN SPORE support, first through a Developmental Research Program award and later following elevation to Continuing Project 1, we have identified a connection between tumor metabolism, hypoxia and T cell dysfunction that may be partially driving resistance to anti-PD-1 (Zandberg, et al, ASCO 2020). To further investigate this question, we are proposing to conduct two newly designed, novel therapeutic clinical trials within Project 1, in R/M HNSCC naïve to anti-PD-1 (HCC 18-190/NCT04114136) or progressed on anti-PD-1 (HCC 18-156/NCT04326257). The former is a trial of metabolic modulators and anti- PD1, the latter a trial of anti-PD-1 combined with either anti-CTLA4 or anti-LAG3. Utilizing these trials and pre- clinical models of HNSCC, we will examine the following questions. First, what is the relationship between anti-PD-1 resistance, tumor metabolism and hypoxia in HNSCC? With the assistance of Core B, we will address this question via multiplexed tissue analysis in R/M HNSCC samples from our clinical trials as well as radiomics-based approaches of determining tumor hypoxia. Second, does hypoxia promote resistance to combinatorial immunotherapy in HNSCC? We will test how hypoxia may impede immunotherapy with nivolumab plus relatlimab (anti-LAG3), or ipilimumab (anti-CTLA4) in R/M HNSCC patients who have progressed on anti-PD-1, evaluating tissue before and after therapy. Third, can metabolically targeted therapy be combined with anti-PD-1 to overcome anti-PD1 resistance in HNSCC? We will evaluate tumor samples obtained before and after treatment with anti-PD-1 plus either metformin or rosiglitazone and determine changes in tumor metabolism and hypoxia. We will also test combinatorial immunotherapy (as in Aim 2) with metabolic modulation in pre-clinical HNSCC models rendered anti-PD1 resistant. Our trial of metabolic inhibitors combined with anti-PD1 therapy, if positive, will directly lead to larger scale clinical studies, opening up an entirely novel avenue of combinatorial immunotherapy; while the project as a whole will also provide a platform for developing future personalized immunotherapy trials by adding metabolic analysis and/or modulation as a component.

项目摘要 - 项目1 在复发和转移性头颈部颈部颈部颈部细胞癌（R/M HNSCC）中，免疫检查点 封锁改变了护理标准，并进行了HN Spore Pi Robert Ferris博士和Co-I的试验（项目 2）芭芭拉·伯特斯（Barbara Burtness）博士在这种情况下开创了抗PD-1的使用。 由于对抗PD-1疗法的抵抗，患者受益于迫切需要更好地了解您 肿瘤微环境。 后来在持续项目1的海拔后，我们已经确定了肿瘤之间的联系 代谢，缺氧和T细胞功能障碍可能是副驱动抗PD-1的抗药性（Zandberg，ET Al，ASCO 2020）。 项目1中的治疗临床试验，r/m hnscc天真的抗PD-1（HCC 18-190/NCT04114136）或或或或 在抗PD-1上进行（HCC 18-156/NCT04326257）。 PD1，抗PD-1的试验与抗CTLA4或抗LAG3结合使用。 HNSCC的临床模型，我们将首先检查以下问题。 抗PD-1抗性，肿瘤代谢和HNSCC中的缺氧，我们将在核心B的帮助下 通过我们的临床流量的R/M HNSCC样品中的多路复用组织分析解决此问题 基于放射学的方法，确定肿瘤缺氧的第二种方法。 HNSCC中的联合免疫疗法？ Nivolumab加Relatlimab（抗LAG3）或ipilimumab（抗cultla4）的R/M HNSCC患者 在抗PD-1上进展，评估组织和第三次治疗。 与抗PD-1结合使用，以克服HNSCC中的抗PD1电阻？ 用抗PD-1加二甲双胍或罗格列酮在治疗前后获得，并确定 肿瘤代谢和缺氧的变化。 临床前HNSCC模型中的代谢调制使我们的代谢试验具有抗PD1。 抑制剂结合抗PD1治疗（如果阳性）将直接大规模临床研究，开放 组合免疫疗法的反式新型途径； 通过添加代谢分析和或 调制为组件。