Develop a Therapeutic Nano-vaccine against Head and Neck Cancer

开发针对头颈癌的治疗性纳米疫苗

• 批准号: 10372999
• 负责人: Yu Leo Lei
• 金额: $ 36.68万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10372999
• 关键词: 3-Dimensional; Address; Antigen-Presenting Cells; Antigens; Autophagocytosis; Beds; Biomedical Engineering; Blocking Antibodies; Cancer Detection; Cancer Patient; Cell Line; Cell Proliferation; Cells; Cellular biology; Clinical; Cross-Priming; Cytotoxic T-Lymphocytes; Defect; Deglutition; Detection; Disease Progression; Effector Cell; Engineering; Exhibits; Failure; Generations; Genes; Goals; Half-Life; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Homing; Human; Human Papillomavirus; Immune; Immune Tolerance; Immune checkpoint inhibitor; Immunity; Immunology; Immunotherapy; Implant; In Vitro; Infiltration; Interferon Type I; Interferon-beta; Interferons; Jaw; Lockjaw; Lymphocyte Function; Malignant Neoplasms; Mediating; Modeling; Monoclonal Antibodies; Morbidity - disease rate; Mycoses; Neoadjuvant Therapy; Oncogenes; Oral; Pathway interactions; Patients; Prognosis; Regimen; Resistance; Resistance development; Role; STING agonists; Signal Transduction; Sting Injury; Surgical Management; System; T-Lymphocyte; Technology; Testing; Tissue Microarray; Tumor Antigens; Tumor Burden; Tumor Expansion; Tumor Immunity; Tumor-Infiltrating Lymphocytes; Tumor-infiltrating immune cells; Vaccines; Xerostomia; adaptive immunity; anti-tumor immune response; antigen-specific T cells; biomaterial compatibility; bone; cancer cell; checkpoint receptors; chemoradiation; cytotoxic CD8 T cells; cytotoxicity; density; efficacy evaluation; exhaust; follow-up; head and neck cancer patient; immune activation; immune checkpoint; immune checkpoint blockade; immunogenic; immunogenicity; improved functioning; in vivo; innovation; malignant mouth neoplasm; nanotherapeutic; nanovaccine; neoantigens; neoplastic cell; novel strategies; patient subsets; prototype; public health relevance; receptor; resistance mechanism; response; stem; success; targeted treatment; trafficking; transcriptome sequencing; tumor; tumor growth; tumor microenvironment; tumor-immune system interactions; vaccine efficacy

PROJECT SUMMARY Clinical success of immune checkpoint receptor (ICR) blockade stems from its efficacy in restoring the effector function of exhausted tumor-infiltrating lymphocytes. But an exclusive effector immune cell-targeted treatment is prone to failure in hypoimmunogenic cold tumors, which are featured by insufficient elicitation of tumor-specific T-cell immunity and resistance to immunogenic cytotoxicity. Indeed, about 80% of Oral, Head & Neck Squamous Cell Carcinoma (HNC) patients do not respond to ICR blockade. Conventional chemoradiotherapy and surgical management are associated with high morbidity, such as swallowing problems, dry mouth, fungal infection, dead bone of the jaw, disfigurement, and “lock-jaw”. Deescalating treatment results in disease progression. Thus, it is urgent to characterize the mechanisms underpinning HNC hypoimmunogenicity. Our preliminary study identifies type I interferon signaling in the tumor microenvironment as a key pathway modulating the plasticity of anti-tumor immune response. Type I interferon target genes promote antigen-presenting cell (APC) and effector cell trafficking to the tumor bed, and enhance APC cross- priming efficiency. To mitigate the negative impact of cold HNC upon immune activation, we engineered a nano-vaccine system that potently enhances type I interferon signaling and antigen delivery. Our prototype nano-vaccine leads to an over 12-fold expansion of tumor-specific T cells in the tumor microenvironment, and significantly reduces tumor burden. Informed by our results and in response to the FOA, the overarching hypothesis of the project is: type I interferon signaling is essential to maintain HNC immunogenicity, and our nano-vaccine sensitizes cold HNC to ICR blockade. To test this hypothesis, three aims are put in place: **(1) we will characterize the role of type I interferon signaling in modulating HNC immunogenicity; **(2) we will determine the mechanisms HNC cells employ to dampen type I interferon signaling and promote resistance to checkpoint blockade; **(3) we will optimize a type I interferon-inducing tumor-specific nano-vaccine system to break HNC immune tolerance. These goals are in precise alignment with the FOA. (1) We will elucidate the role of type I interferon signaling in modulating the plasticity of anti-tumor immunity. (2) We will develop a safe, biocompatible, highly immunogenic and effective nano-vaccine technology to precisely and predictably enrich tumor antigen-specific T-cell repertoire.

项目摘要 免疫切解点受体（ICR）阻滞步骤的临床成功，距恢复效率 耗尽的肿瘤浸润淋巴细胞的效应函数。但是独家效应子免疫细胞靶向 治疗容易在低免疫原性冷肿瘤中失败，这是由于不足 肿瘤特异性T细胞免疫组织化学和对免疫原性细胞毒性的抗性。确实，大约80％的口服，头部＆ 颈部方形细胞癌（HNC）患者对ICR封锁没有反应。传统的 化学放疗和手术管理与高发病率有关，例如吞咽 问题，口干，真菌感染，下颌的死骨，毁容和“锁定”。降低的 治疗导致疾病进展。这是迫切表征HNC支撑的机制 低免疫原性。我们的初步研究确定了肿瘤微环境中I型干扰素信号传导 作为调节抗肿瘤免疫反应的可塑性的关键途径。 I型干扰素靶基因 促进抗原呈递细胞（APC）和效应细胞运输到肿瘤床，并增强APC交叉 启动效率。为了减轻感冒HNC在免疫激活时的负面影响，我们设计了一个 纳米疫苗系统可能会增强I型干扰素信号传导和抗原递送。我们的原型 纳米疫苗会导致肿瘤微环境中肿瘤特异性T细胞的12倍膨胀，并且 大大减轻了肿瘤负担。根据我们的结果和回应FOA的响应，总体 该项目的假设是：I型干扰素信号对于维持HNC免疫原性至关重要，我们 纳米vaccine感应冷HNC对ICR阻滞。为了检验这一假设，提出了三个目标：**（1） 我们将表征I型干扰素信号在调节HNC免疫原性中的作用； **（2）我们会的 确定HNC细胞的机制员工到达梅型I型干扰素信号传导，并促进对 检查点封锁； **（3）我们将优化一种I型干扰素诱导肿瘤特异性纳米疫苗系统 打破HNC免疫耐受性。这些目标是与FOA的准确对齐。 （1）我们将阐明 I型干扰素信号传导在调节抗肿瘤免疫的可塑性中的作用。 （2）我们将开发一个安全的 生物相容性，高度免疫原性和有效的纳米疫苗技术，可精确且可预测 肿瘤抗原特异性T细胞曲目。