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: 10331957
• 负责人: Greg M. Delgoffe
• 金额: $ 31.71万
• 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/10331957
• 关键词: Address; Affect; Aftercare; American Society of Clinical Oncology; Animals; Automobile Driving; Award; Cell physiology; Cells; Clinical; 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; Immunity; Immunologics; Immunotherapy; Lead; Malignant Neoplasms; Metabolic; Metabolism; Metastatic/Recurrent; Metformin; Minority; Modeling; Nivolumab; Outcome; Oxidative Phosphorylation; Patients; Pharmaceutical Preparations; Phenotype; Pre-Clinical Model; Recurrence; Reproduction spores; Research; Research Personnel; Resistance; Sampling; Scanning; T-Lymphocyte; Testing; Therapeutic Clinical Trial; Tissues; Tumor Immunity; Tumor-infiltrating immune cells; X-Ray Computed Tomography; anti-CTLA4; anti-PD-1; anti-PD1 therapy; base; cell type; checkpoint inhibition; combinatorial; design; 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 在复发和转移性的头和颈部鳞状细胞癌（R/M HNSCC）中，免疫切口点 盖废包已改变了护理标准，并接受了HN Spore Pi Robert Ferris博士和Co-I的试验（Project 2）芭芭拉·伯特尼斯（Barbara Burtness）博士在这种情况下开创了抗PD-1的使用。不幸的是，只有少数 由于对抗PD-1疗法的抵抗，患者受益，这表明迫切需要更好地了解 肿瘤微环境。在HN孢子的支持下，首先要通过发展研究计划奖 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细胞功能障碍可能部分推动抗PD-1的抗性（Zandberg，ET Al，ASCO 2020）。为了进一步调查这个问题，我们提议进行两个新设计的新型新颖 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 在抗PD-1（HCC 18-156/NCT04326257）上进行进展。前者是代谢调节剂和抗 - 的试验 PD1，后者是抗PD-1的试验，结合了抗CTLA4或抗LAG3。利用这些试验和预先 HNSCC的临床模型，我们将研究以下问题。首先，是什么关系 HNSCC中的抗PD-1耐药性，肿瘤代谢和缺氧？在核心B的帮助下，我们将 通过我们的临床试验中的R/M HNSCC样品中的多路复用组织分析解决此问题 确定肿瘤缺氧的基于放射学的方法。其次，缺氧会促进对 HNSCC中的组合免疫疗法？我们将测试缺氧如何阻止免疫疗法 nivolumab加Relatlimab（抗LAG3）或ipilimumab（抗CTLA4）的R/M HNSCC患者 在抗PD-1上进展，在治疗前后评估组织。第三，可以代谢靶向治疗 与抗PD-1结合以克服HNSCC中的抗PD1抗性？我们将评估肿瘤样品 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。我们还将与 临床前HNSCC模型中的代谢调节具有抗PD1的抗性。我们的代谢试验 抑制剂结合抗PD1治疗（如果阳性）将直接导致更大的临床研究，开放 建立一条完全新颖的组合免疫疗法途径；虽然整个项目也将提供 通过添加代谢分析和/或 调制为组件。