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

摘要 对于HPV阴性的头颈部癌症患者，目前的治疗方法并不能导致Sigg-2的产生。 寿命长，大多数人死于原发肿瘤的局部区域复发。我们发现 根据PD-L1和CD8的状态，HPV(-)头颈部癌症患者适合四个不同的类别。 这些类别有不同的结果，如局部区域复发和特定疾病的存活率， CD8和PDL-1双阳性患者的情况比任何其他患者队列都要差。我们问过我们能不能- 可利用这些患者类别的独特生物学特征的FELL治疗策略。我们假设普拉斯- PDL-1的作用要么阻断CD8细胞毒性T细胞的渗透，要么导致产生 转移到肿瘤实质。进一步的假设，我们询问表面PDL-1的过度表达是否可以用作 金纳米粒子辐射增敏的寻的机理。我们还询问了阻断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。在这份提案中，我们主要问了三个问题：1)我们能否使用PDL-1来购买黄金 纳米粒子和增强肿瘤细胞内的辐射？我们假设过度表达 PDL-1可作为放射增敏的理想归巢策略。金纳米粒子被很好地描述 容易通过抗体靶向肿瘤的放射增敏剂。我们将结合球形的金纳米粒子 给α-pDL-1，并检测它们在体内对肿瘤控制和总生存期的有效性。2)通过什么机制 PDL-1阻断细胞毒T细胞的活性，这一机制能被推翻吗？使用 头颈部癌的同基因模型，我们将研究是否通过基因操作或 抑制性抗体可以改善基因毒性治疗后的肿瘤控制。我们将进一步分析T细胞 从人体组织和动物肿瘤中进行渗透，并询问在PDL-1作用下- 展示会。我们的目标是了解肿瘤细胞中PDL-1的过度表达是否简单地与 全身性免疫抑制。3)辐射能提高垂死肿瘤细胞的免疫原性吗？我们呈现的是 数据表明，具有高线性转移能(LET)的辐射可以通过粒子实现 治疗，在体外增加来自肿瘤细胞的免疫原信号。因此，我们将调查是否治疗 具有高LET的质子束在体内也能达到类似的效果。最后，作为对三支安打策略的测试， 我们将研究通过将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细胞的耗竭，增强辐射效应。 融合，并增加死亡肿瘤细胞的免疫原性。我们对肿瘤之间相互作用的认识 生物学和免疫系统表明，必须开发新的策略，将我们的 将纳米技术、辐射反应和免疫学知识转化为尖端和创新的治疗方法- 管理策略。

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.