Nanoparticle-Modulated Response Against Tumor-Associated Antigens

描述（由申请人提供）：癌症治疗提高了生存率并延迟了肿瘤复发，但多药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身体的天然免疫系统来识别和摧毁癌细胞。临床试验已经研究了使用来自肿瘤相关抗原的肽表位的可行性。虽然这些办法很有希望，但很少引起足够强烈的反应。 我们的长期目标是开发一种蛋白质纳米颗粒技术平台，旨在提高免疫系统识别和破坏表达肿瘤相关抗原的癌细胞的天然能力。具体而言，我们专注于靶向癌症/睾丸（CT）类抗原。在这项拟议的工作中，我们将研究的前提是，针对癌细胞的免疫反应的幅度和类型，可以更有效地引起时，CT抗原耦合到最佳摄取大小的纳米粒子，同时与树突状细胞激活剂分子功能化。我们预计，通过将这些元素组合在纳米颗粒中，同时的空间和时间给药将产生协同效应，从而显着提高治疗效果。为了验证这一假设，我们提出了以下具体目标：（1）制备用CT抗原和树突状细胞活化剂两者功能化的蛋白质纳米颗粒;（2）评价由于携带单个CT抗原表位的蛋白质纳米颗粒引起的细胞毒性T淋巴细胞应答、体内细胞因子产生和调节性T细胞活性;和（3）由于携带多个CT抗原表位的蛋白质纳米颗粒，评价细胞毒性T淋巴细胞应答、体内细胞因子产生和调节性T细胞活性。 这项工作将评估使用基于纳米颗粒的策略的可行性，该策略有可能显着提高治疗效果，并产生使用此类技术改进癌症疫苗的一般原则。它将确定是否可以通过将抗原，免疫激活剂和被动靶向整合在单个实体中来实现更有效的免疫治疗。最终，我可以潜在地提供一种新的，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.