Strategies to Overcome Immune Resistance in Head and Neck Cancers

摘要--总体计划 头颈部鳞状细胞癌(HNSCC)是一个世界性的公共卫生问题和癌症患者 有效的治疗选择有限。50年来，总体生存第一次受到了 HNSCC患者接受FDA批准的抗PD1单药治疗。然而，只有HNSCC的一小部分 患者可从临床获益。我们计划的目标是在以下项目的逐步成功的基础上再接再厉 免疫治疗和通过解决实现临床的两个主要障碍来改善临床结果 对免疫治疗的反应：(A)肿瘤整体抗原性较差(内在机制)，这限制了 产生抗肿瘤免疫，以及(B)先天和适应性免疫抑制(外在机制) 导致免疫耐受。该计划项目的总体目标(P01)是为了获得进一步的洞察力 探讨HNSCC免疫耐药的两种机制，从而通过合理的 新的组合免疫治疗策略的设计和快速翻译最终将 增加可能从免疫治疗中获得临床益处的HNSCC患者的数量。至 为了实现这些目标，本方案力求实现以下总体目标： 总体目标1：揭示HNSCC免疫耐药的内在和外在机制 病人。 总体目标2：开发理论基础、新的组合策略，转化为临床应用 有意义的回应。 这些目标利用了概念和方法的创新，并结合了Head和 颈部肿瘤学，人类白细胞抗原生物学，抗原肽发现，淋巴细胞和髓系细胞生物学， 基因组学/表观基因组学、抗体药物结合疗法和小鼠模型。总体目标将是 实施了3个相互关联和重点突出的项目和3个共享资源核心： -项目1：通过表观遗传重新编程从治疗上提高HNSCC的抗原性(Pai博士) -项目2：通过APECS将先前存在的抗病毒免疫重新定向到HNSCCs(Cobbold博士) -项目3：HNSCC治疗中的髓系淋巴细胞串扰(皮特博士) -行政核心(Pai/Wirth博士) -核心1：诊断免疫病理学和成像核心(Sadow/Faquin博士) 核心2：免疫生物信息学和计算生物学核心(泽维尔博士/萨托博士) 在五年结束时，我们的目标是启动几个组合策略的临床试验 头颈部癌症患者，这将以本P01产生的数据为基础。我们期待着 总体规划将对头颈部癌症患者的临床结果产生重大影响 它的发现也有可能影响更大的免疫肿瘤学领域。

SUMMARY - OVERALL PROGRAM Head and neck squamous cell carcinoma (HNSCC) is a worldwide public health problem and cancer patients have limited effective treatment options. For the first time in 50 years, overall survival has been impacted in HNSCC patients with the FDA approval of anti-PD1 monotherapy. However, only a small subset of HNSCC patients derives clinical benefit. The goal of our Program is to build upon the incremental successes of immunotherapy and improve clinical outcomes by addressing the two main barriers to achieving clinical response to immunotherapy: (a) the tumor's overall poor antigenicity (intrinsic mechanism), which limits the generation of antitumor immunity, and (b) innate and adaptive immune suppression (extrinsic mechanism) that results in immune tolerance. The overarching goal of this Program Project (P01) is to gain further insight into both mechanisms of HNSCC immune resistance, so as to overcome them through the rational design and rapid translation of novel combinatorial immunotherapeutic strategies which will eventually increase the number of HNSCC patients who may derive clinical benefit from immunotherapy. To accomplish these goals, the Program seeks to achieve the following overall aims: Overall Aim 1: Uncover both intrinsic and extrinsic mechanisms of immune resistance in HNSCC patients. Overall Aim 2: Develop rationale, novel combinatorial strategies that translate into clinically meaningful responses. These aims leverage innovations in concepts and methodology and are coupled with expertise in head and neck oncology, HLA biology, antigenic peptide discovery, lymphocyte and myeloid cell biology, genomics/epigenomics, antibody drug conjugate therapy, and mouse modeling. The broad aims will be implemented with 3 inter-related and focused Projects and 3 Shared Resource Cores: - Project 1: Therapeutically improving HNSCC antigenicity through epigenetic reprogramming (Dr. Pai) - Project 2: Redirecting pre-existing anti-viral immunity to HNSCCs with APECs (Dr. Cobbold) - Project 3: Myeloid-lymphoid cell crosstalk in HNSCC therapy (Dr. Pittet) - Administrative Core (Drs. Pai/Wirth) - Core 1: Diagnostic Immunopathology and Imaging Core (Drs. Sadow/Faquin) - Core 2: Immune Bioinformatics and Computational Biology Core (Drs. Xavier/Sartor) At the end of the 5 years, we aim to have initiated several clinical trials of combinatorial strategies in head and neck cancer patients, which will be grounded on the data generated from this P01. We expect the overall Program will have a significant impact on the clinical outcomes of head and neck cancer patients and its discoveries also have the potential to impact the larger immuno-oncology field.