Nanoparticle-Modulated Response Against Tumor-Associated Antigens

描述(申请人提供)：癌症治疗提高了存活率，延缓了肿瘤复发，但多重耐药和转移等挑战仍可能破坏标准疗法。出于这个原因，免疫介导的方法专注于招募人体的天然免疫系统来识别和摧毁癌细胞。临床试验已经调查了使用肿瘤相关抗原的多肽表位的可行性。尽管这些方法一直很有希望，但它们很少引起足够强烈的回应。我们的长期目标是开发一个蛋白质纳米颗粒技术平台，旨在提高免疫系统识别和摧毁表达肿瘤相关抗原的癌细胞的天然能力。具体地说，我们专注于针对癌症/睾丸(CT)类抗原。在这项拟议的工作中，我们将检验这样一个前提，即当CT抗原与具有最佳摄取大小的纳米颗粒偶联时，可以更有效地激发针对癌细胞的免疫反应的大小和类型，这些纳米颗粒同时具有树突状细胞激活分子的功能。我们预计，通过在纳米颗粒中结合这些元素，同时进行空间和时间剂量将产生协同效应，从而显著提高治疗效果。为了验证这一假设，我们提出了以下具体目标：(1)构建同时具有CT抗原和树突状细胞激活剂的蛋白质纳米颗粒；(2)评估含有单一CT抗原表位的蛋白质纳米颗粒对细胞毒性T淋巴细胞的反应、体内细胞因子的产生和调节性T细胞的活性；以及(3)评价含有多个CT抗原表位的蛋白质纳米颗粒的细胞毒性T淋巴细胞反应、体内细胞因子的产生和调节性T细胞的活性。这项工作将评估使用基于纳米颗粒的战略的可行性，这种战略有可能显著提高治疗效率，并产生利用此类技术改进癌症疫苗的一般原则。它将决定是否可以通过在单一实体内集成抗原、免疫激活剂和被动靶向来实现更有效的免疫治疗。最终，我可能会提供一种新的、更有效的治疗策略，适用于传统上难以治疗的癌症状态。

DESCRIPTION (provided by applicant): Treatment for cancer has improved survival and delayed tumor recurrence, but challenges such as multidrug resistance and metastasis can still undermine standard therapies. For this reason, immune-mediated approaches focus on recruiting the body's native immune system to recognize and destroy cancer cells. Clinical trials have investigated the feasibility of using peptide epitopes from tumor-associated antigens. Although these approaches have been promising, they rarely invoke a sufficiently strong response. Our long-term goal is to develop a protein nanoparticle technology platform designed to increase the immune system's native ability to recognize and destroy cancer cells expressing tumor-associated antigens. Specifically, we are focused on targeting the cancer/testis (CT) class of antigens. In this proposed work, we will examine the premise that the magnitude and type of immune responses against cancer cells can be more effectively elicited when CT antigens are coupled to nanoparticles of optimal uptake size that are simultaneously functionalized with a dendritic cell-activator molecule. We expect that by combining these elements in a nanoparticle, simultaneous spatial and temporal dosing will yield synergistic effects, thereby improving therapeutic efficacy significantly. To examine this hypothesis, we propose the following specific aims: (1) Fabrication of protein nanoparticles that are functionalized with both CT antigens and a dendritic cell activator; (2) Evaluation of the cytotoxi T-lymphocyte response, in vivo cytokine production, and regulatory T cell activity due to protein nanoparticles bearing a single CT antigen epitope; and (3) Evaluation of the cytotoxic T- lymphocyte response, in vivo cytokine production, and regulatory T cell activity due to protein nanoparticles bearing multiple CT antigen epitopes. This work will evaluate the feasibility of using a nanoparticle-based strategy that has the potential to significantly increase treatment efficacy and to generate general principles for improving cancer vaccines using such technologies. It will determine whether more effective immunotherapy can be achieved by integrating antigens, immune activator, and passive targeting within a single entity. Ultimately, i can potentially provide a new, more effective therapeutic strategy applicable for cancer states that are conventionally difficult to treat.