Strategies to Overcome Immune Resistance in Head and Neck Cancers

克服头颈癌免疫抵抗的策略

• 批准号: 10478890
• 负责人: Sara Isabel Pai
• 金额: $ 170.25万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-19 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10478890
• 关键词: Address; Anti-CD40; Antibody-drug conjugates; Bioinformatics; Biological; Biology; Biopsy; Cancer Patient; Cells; Cellular biology; Clinic; Clinical; Clinical Trials; Community Clinical Oncology Program; Computational Biology; Coupled; DNA Methyltransferase Inhibitor; Data; Diagnostic; Discipline; Drug or chemical Tissue Distribution; Ensure; Epigenetic Process; Epitopes; Foundations; Generations; Genomics; Goals; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Head and neck structure; Histocompatibility Antigens Class I; Image; Immune; Immune Tolerance; Immune system; Immunomodulators; Immunooncology; Immunosuppression; Immunotherapeutic agent; Immunotherapy; Investigation; Lymphocyte; Lymphoid Cell; Methodology; Myelogenous; Myeloid Cells; Oncology; Outcome; Pathway interactions; Patients; Peptide antibodies; Peptides; Public Health; Research; Research Personnel; Resistance; Resource Sharing; Sampling; Squamous cell carcinoma; Testing; Therapeutic; Time; Tissue Banks; Tissues; Translating; Translations; Tumor Antigens; Tumor Immunity; Tumor-infiltrating immune cells; Up-Regulation; anti-PD-1; anti-tumor immune response; antigen processing; antiviral immunity; arm; clinically relevant; combinatorial; effective therapy; epigenomics; head and neck cancer patient; immune resistance; immunopathology; improved; innovation; insight; large datasets; mouse model; novel; pre-clinical; programs; rational design; resistance mechanism; response; response biomarker; success; tumor

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.

摘要-总体说明 头颈部鳞状细胞癌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，总体生存率首次受到影响 FDA批准抗PD 1单药治疗的HNSCC患者。然而，只有一小部分HNSCC 患者获得临床益处。我们的计划的目标是建立在以下方面的逐步成功的基础上： 通过解决实现临床治疗的两个主要障碍， 对免疫治疗的反应：（a）肿瘤的整体抗原性差（内在机制），这限制了免疫治疗的效果。 产生抗肿瘤免疫，和（B）先天性和适应性免疫抑制（外在机制）， 导致免疫耐受。本计划项目（P01）的首要目标是获得进一步的见解 HNSCC免疫抵抗的两种机制，以便通过合理的免疫治疗来克服它们。 设计和快速翻译新的组合免疫策略， 增加可能从免疫治疗中获得临床益处的HNSCC患者的数量。到 为实现这些目标，该方案力求实现以下总体目标： 总体目标1：揭示HNSCC中免疫抵抗的内在和外在机制 患者 总体目标2：开发合理的、新的组合策略， 有意义的回答。 这些目标利用概念和方法的创新，并与头部和头部的专业知识相结合， 颈部肿瘤学，HLA生物学，抗原肽发现，淋巴细胞和骨髓细胞生物学， 基因组学/表观基因组学、抗体药物缀合物疗法和小鼠建模。广泛的目标将是 通过3个相互关联的重点项目和3个共享资源核心来实施： - 项目1：通过表观遗传重编程治疗性改善HNSCC抗原性（派博士） - 项目2：将预先存在的抗病毒免疫重定向至具有APEC的HNSCC（Cobbold博士） - 项目3：HNSCC治疗中的骨髓-淋巴细胞串扰（Pittet博士） - 行政核心（派博士/Wirth） - 核心1：诊断免疫病理学和成像核心（Drs. Sadow/Faquin） - 核心2：免疫生物信息学和计算生物学核心（Xavier/Sartor博士） 在5年结束时，我们的目标是启动几项组合策略的临床试验， 头颈部癌症患者，其将基于从该P01生成的数据。我们预计 整个计划将对头颈癌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。