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: 9895433
• 负责人: Yu Leo Lei
• 金额: $ 37.05万
• 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 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9895433
• 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; 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; 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; outcome forecast; 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 免疫检查点受体（ICR）阻断的临床成功源于其在恢复免疫功能方面的功效。 耗尽的肿瘤浸润淋巴细胞的效应子功能。但是一种专门的效应免疫细胞靶向 治疗在低免疫原性冷肿瘤中容易失败，其特征在于不充分的诱导， 肿瘤特异性T细胞免疫和对免疫原性细胞毒性的抗性。事实上，大约80%的口腔，头部和 颈部鳞状细胞癌（HNC）患者对ICR阻断无反应。常规 放化疗和手术治疗与高发病率相关，如吞咽 问题，口干，真菌感染，颌骨死骨，毁容，和“锁颌”。降级 治疗导致疾病进展。因此，迫切需要描述HNC的机制 低免疫原性我们的初步研究确定了肿瘤微环境中的I型干扰素信号传导 作为调节抗肿瘤免疫应答可塑性的关键途径。I型干扰素靶基因 促进抗原提呈细胞（APC）和效应细胞向肿瘤床的运输，并增强APC跨- 启动效率为了减轻冷HNC对免疫激活的负面影响，我们设计了一种新的HNC。 纳米疫苗系统，有效地增强I型干扰素信号传导和抗原递送。我们的原型 纳米疫苗导致肿瘤微环境中肿瘤特异性T细胞扩增超过12倍， 显著降低肿瘤负荷。根据我们的结果和对FOA的回应， 该项目的假设是：I型干扰素信号传导对于维持HNC免疫原性是必不可少的，并且我们的 纳米疫苗使冷HNC对ICR阻断敏感。为了验证这一假设，我们设定了三个目标：**（1） 我们将描述I型干扰素信号在调节HNC免疫原性中的作用; **（2）我们将 确定HNC细胞用于抑制I型干扰素信号传导和促进抗干扰素的机制。 检查点阻断; **（3）我们将优化I型干扰素诱导的肿瘤特异性纳米疫苗系统， 破坏HNC免疫耐受。这些目标与《行动纲领》完全一致。(1)我们将阐明 I型干扰素信号在调节抗肿瘤免疫可塑性中的作用。(2)我们将开发一个安全， 生物相容性，高免疫原性和有效的纳米疫苗技术，以精确和可预测地富集 肿瘤抗原特异性T细胞库。