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

项目概要-项目1 在复发性和转移性头颈部鳞状细胞癌（R/M HNSCC）中， 阻断已经改变了护理标准，来自HN SPORE PI的Robert Ferris博士和co-I（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 患者受益，由于抗PD-1治疗的耐药性，指出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，在升级到继续项目1之后，我们已经确定了肿瘤与癌症之间的联系， 代谢、缺氧和T细胞功能障碍可能部分驱动抗PD-1的抗性（Zandberg，et 等人，ASCO 2020）。为了进一步研究这个问题，我们建议进行两个新设计的，新颖的， 项目1内的治疗性临床试验，在抗PD-1初治的R/M HNSCC（HCC 18-190/NCT 04114136）或 抗PD-1治疗进展（HCC 18-156/NCT 04326257）。前者是代谢调节剂和抗- PD 1，后者是抗PD-1与抗CTLA 4或抗LAG 3组合的试验。利用这些试验和预- HNSCC的临床模型，我们将研究以下问题。第一，什么是关系 抗PD-1耐药，肿瘤代谢和缺氧在HNSCC？在核心B的协助下，我们将 通过对来自我们临床试验的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。第二，缺氧是否会促进对 HNSCC的联合免疫治疗我们将测试缺氧如何阻碍免疫治疗， 纳武单抗加relatlimab（抗LAG 3）或ipilimumab（抗CTLA 4）治疗具有以下特征的R/M HNSCC患者 抗PD-1治疗进展，评估治疗前后的组织。第三，代谢靶向治疗 与抗PD-1联合治疗，以克服HNSCC的抗PD 1耐药性？我们将评估肿瘤样本 在抗PD-1加二甲双胍或罗格列酮治疗前后获得，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）， 在临床前HNSCC模型中的代谢调节使得抗PD 1具有抗性。我们的代谢试验 抑制剂联合抗PD 1治疗，如果阳性，将直接导致更大规模的临床研究， 开辟了一条全新的组合免疫疗法途径;而该项目作为一个整体也将提供一个 通过增加代谢分析和/或免疫治疗试验，开发未来个性化免疫治疗试验的平台 调制作为一种成分。

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.