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.

项目概要 免疫检查点受体（ICR）阻断的临床成功源于其恢复免疫功能的功效。 耗尽的肿瘤浸润淋巴细胞的效应功能，而是一种专门针对免疫细胞的效应功能。 低免疫原性冷肿瘤的治疗很容易失败，其特点是诱导不足 事实上，约 80% 的肿瘤特异性 T 细胞免疫和免疫原性细胞毒性的抵抗力。 颈部鳞状细胞癌 (HNC) 患者对传统的 ICR 阻断没有反应。 放化疗和手术治疗与高发病率相关，例如吞咽 问题、口干、真菌感染、下颌死骨、毁容和“下颌锁紧”。 治疗会导致疾病进展，因此迫切需要了解 HNC 的机制。 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反应可塑性的关键途径。 促进抗原呈递细胞 (APC) 和效应细胞运输至肿瘤床，并增强 APC 交叉 为了减轻冷 HNC 对免疫激活的负面影响，我们设计了一种 纳米疫苗系统可有效增强 I 型干扰素信号传导和抗原递送。 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，并且 根据我们的结果以及对 FOA 的总体反应，显着降低了肿瘤负担。 该项目的假设是：I 型干扰素信号传导对于维持 HNC 免疫原性至关重要，而我们的 纳米疫苗使冷 HNC 对 ICR 封锁敏感 为了检验这一假设，我们制定了三个目标：**(1)。 我们将描述 I 型干扰素信号传导在调节 HNC 免疫原性中的作用 **(2) 我们将 确定 HNC 细胞抑制 I 型干扰素信号传导和促进耐药性的机制 检查点封锁；**（3）我们将优化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。这些目标与 FOA (1) 精确一致。 I型干扰素信号在调节抗肿瘤免疫可塑性中的作用（2）我们将开发一种安全的、 生物相容性、高免疫原性和有效的纳米疫苗技术，可精确、可预测地丰富 肿瘤抗原特异性 T 细胞库。