Enhancing Tumor Antigen Presentation with Complement Targeted Nanoparticles

项目总结/摘要 活化的抗原呈递细胞（APC）吞噬并向T细胞展示肿瘤抗原，启动免疫应答。 对抗癌症的反应。然而，在癌症患者中，APC通常被免疫抑制，导致 抑制T细胞、促进肿瘤生长和在实体恶性肿瘤中免疫治疗失败。目前， 没有能够将APC活化为免疫刺激表型的临床治疗选择， 同时递送肿瘤抗原以驱动抗原呈递和抗肿瘤免疫。没有新 尽管有增强抗原呈递的方法，但癌症免疫疗法可能继续局限于小规模的免疫治疗。 患者的百分比。在一个重要的进步，我们的实验室已经开发了脂质体输送系统（C3- 脂质体）可以靶向所有三种APC：树突细胞、巨噬细胞和B细胞（Francian， 2017年）。此外，初步结果表明，C3-脂质体递送肿瘤抗原和活化 在小鼠癌症模型中，将化合物与APC结合，导致T细胞活化和肿瘤消除。的 已经确定了以下使用C3-脂质体改善肿瘤抗原呈递的策略。 目的1：评价对抗原和TLR激动剂组合的C3-脂质体递送的免疫应答。 导致抗原呈递细胞活化的Toll样受体（TLR）激动剂将包封在 C3-脂质体沿着与MHCI和MHCII结合卵清蛋白（OVA）肽，以确定最佳脂质体浓度。 用于引发免疫应答的制剂。 目的2：使用MUC 1转基因小鼠模型检查C3-脂质体预防效力。在癌症中 在乳腺癌、结直肠癌、胃癌、胃癌等恶性肿瘤中，MUC 1过表达率超过75%， 胰腺、膀胱和其他癌症，使MUC 1成为理想的肿瘤抗原。这一目标的目的是 使用转基因小鼠和肿瘤确定C3-脂质体MUC 1肽递送的预防益处 表达人MUC 1的细胞。 目的3：确定多种肿瘤抗原的C3-脂质体包封是否改善了对 检查点免疫疗法将递送来自B16-F10黑素瘤肿瘤细胞系的多种抗原 与C3-脂质体一起使用，并用检查点阻断免疫疗法进行测试，以确定治疗 黑色素瘤小鼠癌症模型。 提出的目的将评估C3-脂质体用于增强抗原呈递的有效性， 产生对抗癌症的免疫反应与此同时，这项研究还将建立能力， 生物医学研究，并大大加强本科生和研究生的生物医学研究教育 UAA的学生。最终，C3-脂质体可以改善肿瘤抗原的递送，并且当用于 与目前的免疫疗法相结合，增加对治疗有反应的患者的百分比。

PROJECT SUMMARY/ABSTRACT Activated Antigen Presenting Cells (APCs) engulf and display tumor antigen to T cells, initiating the immune response against cancer. However, in cancer patients, APCs are often immune suppressed, resulting in inhibition of T cells, promotion of tumor growth and failure of immunotherapy in solid malignancies. At present, there is no clinical treatment option capable of activating APCs to an immune stimulatory phenotype while simultaneously delivering tumor antigen to drive antigen presentation and antitumor immunity. Without new approaches to enhance antigen presentation, cancer immunotherapy will likely continue to be limited to a small percentage of patients. In a significant step forward, our lab has developed a liposome delivery system (C3- liposomes) that can target all three APCs: dendritic cells, macrophages and B cells (Francian, 2017). Furthermore, preliminary results indicate that C3-liposomes deliver tumor antigen and activating compounds to APCs, leading to T cell activation and elimination of tumors in a murine cancer model. The following strategies have been identified for improving tumor antigen presentation using C3-liposomes. Aim 1: Evaluate immune response to C3-liposome delivery of antigen and TLR agonist combinations. Toll-like receptor (TLR) agonists, which lead to activation of Antigen Presenting Cells, will be encapsulated in C3-liposomes along with MHCI and MHCII binding ovalbumin (OVA) peptides to determine the optimal formulation for eliciting an immune response. Aim 2: Examine C3-liposome prophylactic efficacy using a MUC1 transgenic mouse model. In cancer patients, MUC1 is overexpressed in more than 75% of solid malignancies such as breast, colorectal, stomach, pancreatic, bladder and other cancers, making MUC1 an ideal tumor antigen. The goal of this aim is to determine the prophylactic benefit of C3-liposome MUC1 peptide delivery using transgenic mice and tumors that express human MUC1. Aim 3: Determine if C3-liposome encapsulation of multiple tumor antigens improves responsiveness to checkpoint immunotherapy. Multiple antigens from the B16-F10 melanoma tumor cell line will be delivered with C3-liposomes and tested with checkpoint blockade immunotherapy to determine efficacy in treating a melanoma mouse model of cancer. The proposed aims will evaluate the effectiveness of C3-liposomes for enhancing antigen presentation and creating an immune response against cancer. At the same time, this study will also build capacity for biomedical research and significantly enhance biomedical research education for undergraduate and graduate students at UAA. Ultimately, C3-liposomes could improve tumor antigen delivery and when used in combination with current immunotherapy, increase the percentage of patients who respond to treatment.