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

项目摘要−项目1 在复发和转移的头颈部鳞癌(R/M HNSCC)中，免疫检查点 BLOKADE改变了护理标准，HN孢子皮博士Robert Ferris和co-I(项目)进行了试验 2)芭芭拉·伯尔特斯博士率先在这种情况下使用抗PD-1。不幸的是，只有少数人 患者受益，由于对抗PD-1治疗的抵抗，表明迫切需要更好地了解 肿瘤微环境。在HN孢子支持下，首先通过开发研究计划奖 后来，随着升级到继续项目1，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导致抗PD-1抵抗的部分原因(Zandberg，et Al，ASCO 2020)。为了进一步研究这个问题，我们提议进行两个新设计的，小说 项目1内的治疗性临床试验，R/M HNSCC朴素到抗PD-1(HCC 18-190/NCT04114136)或 抗PD-1(肝癌18-156/NCT04326257)研究进展前者是新陈代谢调节剂和抗肿瘤药物的试验。 PD1，后者是抗PD-1联合抗CTLA4或抗LAG3的试验。利用这些试验和预 关于HNSCC的临床模型，我们将探讨以下问题。第一，两者之间的关系是什么 抗PD-1耐药与HNSCC的肿瘤代谢和缺氧在酷睿B的协助下，我们将 通过对我们临床试验中的R/M HNSCC样本进行多路组织分析来解决这个问题 以放射组学为基础的确定肿瘤缺氧的方法。第二，低氧是否会增强对 HNSCC的联合免疫治疗？我们将测试低氧如何阻碍免疫治疗 Nivolumab联合relatlimab(抗LAG3)或ipilimumab(抗CTLA4)治疗患有 抗PD-1的研究进展，治疗前后的组织评价。第三，新陈代谢靶向治疗 联合抗PD-1以克服HNSCC中抗PD1耐药？我们将评估肿瘤样本 检测抗PD-1抗体联合二甲双胍或罗格列酮治疗前后的变化 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所示) 临床前HNSCC模型中的代谢调节导致抗PD1耐药。我们的新陈代谢试验 抑制剂联合抗PD1治疗，如果呈阳性，将直接导致更大规模的临床研究，开放 开辟了一条全新的组合免疫疗法的途径；而该项目作为一个整体也将提供一种 通过添加代谢分析和/或开发未来个性化免疫治疗试验的平台 作为一个组成部分的调制。

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.