Enhancing immune mediated head and neck cancer anti-tumor activity using nanoparticles

使用纳米粒子增强免疫介导的头颈癌抗肿瘤活性

• 批准号: 9843114
• 负责人: Sunil Krishnan
• 金额: $ 51.86万
• 依托单位: MAYO CLINIC JACKSONVILLE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-20 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9843114
• 关键词: Animals; Antibodies; Apoptosis; Biology; CD8B1 gene; Cancer Patient; Categories; Cell Line; Cells; Cessation of life; Clinical; Clinical Oncology; Clinical Trials; Combined Modality Therapy; Cytotoxic T-Lymphocytes; Data; Disease; Failure; Flow Cytometry; Goals; Gold; Grant; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Head and neck structure; High-LET Radiation; Home; Homing; Human; Human Papillomavirus; Immune; Immune system; Immunodeficient Mouse; Immunology; Immunooncology; Immunotherapy; In Vitro; Infiltration; Knowledge; Lead; Linear Energy Transfer; Longevity; Mediating; Methodology; Modeling; Mus; Nanotechnology; Outcome; Patients; Platinum; Primary Neoplasm; Proteins; Proton Radiation; Radiation; Radiation Oncology; Radiation therapy; Radiation-Sensitizing Agents; Radiosensitization; Recurrence; Sampling; Signal Transduction; Squamous cell carcinoma; Surface; T-Lymphocyte; Testing; Tissues; Translations; Tumor Biology; Tumor-Infiltrating Lymphocytes; Tumor-infiltrating immune cells; Work; anti-cancer; base; bench to bedside; chemokine; chemotherapy; clinical application; cohort; cytokine; cytotoxic CD8 T cells; design; efficacy evaluation; exhaustion; genetic manipulation; genotoxicity; head and neck cancer patient; human tissue; humanized antibody; immunogenic; immunogenicity; improved; in vivo; in vivo Model; innovation; nanoGold; nanoparticle; neoplastic cell; novel; overexpression; particle therapy; programmed cell death ligand 1; proton beam; radiation effect; radiation response; response; standard of care; therapy resistant; treatment strategy; tumor

ABSTRACT For patients with head and neck cancer whose tumors are HPV negative, current therapy does not lead to sig- nificant longevity and most succumb to loco-regional recurrence of the primary tumor. We discovered that HPV(-) head and neck cancer patients fit into four distinct categories relative to their PD-L1 and CD8 status. These categories had discrete outcomes such as loco-regional recurrence and disease-specific survival, with CD8 and PDL-1 double positive patients faring worse than any other patient cohort. We asked if we can de- velop treatment strategies that can leverage the unique biology of these patient categories. We posit that pres- ence of PDL-1 either blocks infiltration of CD8+ cytotoxic T cells or leads to exhaustion of T cells that do make it to the tumor parenchyma. Postulating further, we asked if overexpression of surface PDL-1 can be used as a homing mechanism for radiosensitizing gold nanoparticles. We also asked if blocking PDL-1 could replicate the tumor response of PDL-1 negative cohorts. Finally, we considered strategies that can increase immunogenicity of tumors that lack PDL-1. In this proposal, we ask three main questions: 1) Can we use PDL-1 to home gold nanoparticles and enhance radiation specifically within tumor cells? We hypothesized that overexpression of PDL-1 may serve as the ideal homing strategy for radiosensitization. Gold nanoparticles are well described radiosensitizers that are easily targeted to tumors via antibodies. We will conjugate spheroid gold nanoparticles to α-PDL-1 and examine their efficacy in vivo for tumor control and overall survival. 2) By what mechanism is PDL-1 blocking the activity of infiltrating cytotoxic T cells and can this mechanism be overturned? Using a syngeneic model of head and neck cancer, we will investigate if eliminating PDL-1 by genetic manipulation or an inhibitory antibody can improve tumor control following genotoxic therapy. We will further profile the T cell infiltrate from both the human tissues and the animal tumors and ask if the profile changes following PDL-1 in- hibition. The goal is to understand if PDL-1 overexpression in tumor cells is simply correlative to or causative of the systemic immune inhibition. 3) Can radiation increase immunogenicity of dying tumor cells? We present data to demonstrate that radiation with high linear transfer energy (LET), which can be achieved by particle therapy, increased immunogenic signals from tumor cells in vitro. Therefore, we will investigate if treatment with proton beams with high-LET can achieve a similar effect in vivo. Finally, as a test of a three-hit strategy, we will examine the tumor control that can be achieved by combining α-PDL-1 tagged gold nanoparticles with high-LET proton radiation. We anticipate that this treatment will block T-cell exhaustion, enhance radiation ef- fects, and increase the immunogenicity of dying tumor cells. Our understanding of the interplay between tumor biology and the immune system suggests that new strategies will have to be developed that can merge our knowledge of nanotechnology, radiation response, and immunology into sophisticated and innovative treat- ment strategies.

抽象的 对于肿瘤为HPV阴性的头颈癌患者，当前的治疗不会导致SIG- 寿命很大，最屈服于原发性肿瘤的机车区域复发。我们发现了这一点 相对于其PD-L1和CD8状态，HPV（ - ）头颈癌患者分为四个不同的类别。 这些类别具有离散的结果，例如机车区域复发和疾病特异性生存，并具有 CD8和PDL-1双重阳性患者的表现要比任何其他患者队列差。我们问我们是否可以 可以利用这些患者类别的独特生物学的速度治疗策略。我们肯定 PDL-1的ENCE要么阻止CD8+细胞毒性T细胞的浸润，要么导致T细胞的耗尽 它到肿瘤副群。进一步说明，我们问是否可以将表面PDL-1的过表达用作 放射敏化金纳米颗粒的归巢机制。我们还询问阻止PDL-1是否可以复制 PDL-1阴性队列的肿瘤反应。最后，我们考虑了可以提高免疫原性的策略 缺乏PDL-1的肿瘤。在此提案中，我们提出三个主要问题：1）我们可以使用PDL-1到家黄金 纳米颗粒并在肿瘤细胞中特别增强辐射？我们假设过表达 PDL-1可以作为放射敏化的理想归巢策略。金纳米颗粒被很好地描述 通过抗体容易靶向肿瘤的放射敏剂。我们将结合球形金纳米颗粒 到α-PDL-1并检查其体内效率的肿瘤控制和整体存活。 2）通过什么机制 PDL-1阻断浸润细胞毒性T细胞的活性，该机制是否可以推翻？使用 头颈癌的合成模型，我们将调查是否通过遗传操作消除PDL-1或 抑制性抗体可以改善遗传毒性治疗后的肿瘤控制。我们将进一步介绍T单元 从人体组织和动物肿瘤中渗入 hibition。目的是了解肿瘤细胞中的PDL-1过表达与 系统性免疫。 3）辐射可以增加垂死的肿瘤细胞的免疫原性吗？我们在场 数据以证明具有高线性转移能（LET）的辐射，可以通过粒子实现 治疗，体外肿瘤细胞的免疫原性信号增加。因此，我们将调查是否治疗 具有高质量的质子束可以在体内产生相似的作用。最后，作为对三击战略的测试， 我们将检查可以通过将α-PDL-1标记的金纳米颗粒与 高LET质子辐射。我们预计这种治疗将阻止T细胞疲劳，增强辐射EF- 事实并增加垂死肿瘤细胞的免疫原性。我们对肿瘤之间的相互作用的理解 生物学和免疫系统表明，必须制定新的策略，以合并我们 了解纳米技术，辐射反应和免疫学对复杂和创新治疗的知识 - 提及策略。