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 在复发性和转移性头颈鳞状细胞癌 (R/M HNSCC) 中，免疫检查点 封锁改变了护理标准，HN SPORE PI Dr. Robert Ferris 和 co-I 进行的试验（项目 2) Barbara Burtness 博士率先在这种情况下使用抗 PD-1。不幸的是，只有少数人 由于抗 PD-1 治疗耐药，患者受益，这表明迫切需要更好地了解 肿瘤微环境。在 HN SPORE 的支持下，首先通过发展研究计划奖 后来升级到继续项目 1，我们发现肿瘤之间存在联系 代谢、缺氧和 T 细胞功能障碍可能部分驱动抗 PD-1 耐药性（Zandberg 等 等人，ASCO 2020）。为了进一步研究这个问题，我们建议进行两项新设计的新颖的研究 项目 1 中针对未接受过抗 PD-1 治疗的 R/M HNSCC 的治疗性临床试验 (HCC 18-190/NCT04114136) 或 抗 PD-1 治疗取得进展 (HCC 18-156/NCT04326257)。前者是代谢调节剂和抗氧化剂的试验 PD1，后者是抗 PD-1 与抗 CTLA4 或抗 LAG3 联合的试验。利用这些试验和预 HNSCC 的临床模型，我们将检查以下问题。首先，两者之间有什么关系 HNSCC 的抗 PD-1 耐药、肿瘤代谢和缺氧？在Core B的帮助下，我们将 通过对我们的临床试验中的 R/M HNSCC 样本进行多重组织分析来解决这个问题 基于放射组学的确定肿瘤缺氧的方法。二、缺氧是否会促进抵抗力 HNSCC 的联合免疫治疗？我们将测试缺氧如何阻碍免疫治疗 纳武单抗联合 relatlimab（抗 LAG3）或 ipilimumab（抗 CTLA4）治疗患有以下疾病的 R/M HNSCC 患者： 抗 PD-1 进展，评估治疗前后的组织。三、能否进行代谢靶向治疗 与抗PD-1联合治疗以克服HNSCC的抗PD1耐药性？我们将评估肿瘤样本 在使用抗 PD-1 加二甲双胍或罗格列酮治疗之前和之后获得并确定 肿瘤代谢和缺氧的变化。我们还将测试组合免疫疗法（如目标 2） 临床前 HNSCC 模型中的代谢调节导致抗 PD1 耐药。我们的代谢试验 抑制剂联合抗PD1疗法，如果呈阳性，将直接导致更大规模的临床研究，开启 开辟了一种全新的组合免疫疗法途径；同时该项目作为一个整体也将提供 通过添加代谢分析和/或来开发未来个性化免疫治疗试验的平台 调制作为一个组件。