Cytosolic Delivery of Tumor Antigens into Dendritic Cells

将肿瘤抗原胞质递送至树突状细胞

• 批准号: 9911314
• 负责人: Nicholas L Truex
• 金额: $ 6.49万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9911314
• 关键词: Alleles; Anthrax disease; Antigen Presentation Pathway; Antigen-Presenting Cells; Antigens; Binding; Binding Proteins; Biotechnology; CD8-Positive T-Lymphocytes; Cancer Vaccines; Cell Death; Cell surface; Cells; Clinic; Cytosol; Dana-Farber Cancer Institute; Dendritic Cells; Development; Engineering; Environment; Equipment; Immune response; Immune system; Immunotherapy; In Vitro; Institutes; Lead; Light; Malignant Neoplasms; Mutation; Nature; Patients; Peptide Fragments; Peptides; Play; Polymers; Process; Protein translocation; Proteins; Resources; Role; System; T-Cell Activation; T-Lymphocyte; Tissues; Toxin; Training; Translations; Tumor Antigens; Variant; Work; anthrax lethal factor; anti-cancer; antibody engineering; anticancer research; base; cancer immunotherapy; cell type; design; immune activation; immunogenic; improved; in vivo; nanoparticle; neoantigens; non-Native; novel strategies; novel vaccines; peptide drug; protein aminoacid sequence; small molecule; therapeutic protein; tool; trafficking; tumor; uptake; vaccine delivery

PROJECT SUMMARY/ABSTRACT Cancer vaccines have recently emerged as a selective way to activate T cells against cancer. The treatments are based on peptides, called tumor antigens, derived from peptide sequences in tumors that are immunogenic. Another class of tumor antigens, called neoantigens, arise from mutations in tumors that have not been detected by the immune system. These cancer vaccines with tumor antigens or neoantigens can promote antigen-specific, rather than nonspecific, T-cell activation, by either generating new or amplifying existing immune responses against tumors. Despite the promising anti-cancer immune responses observed with these treatments, effective and selective activation of the immune system remains difficult. Several challenges have limited the translation of cancer vaccines into the clinic: (1) Sufficient uptake of the antigens by antigen presenting cells is difficult to achieve, which greatly influences whether the peptides are processed or presented to T cells. (2) Proteasomal processing of the peptides is difficult to predict, which can result in the formation of peptide fragments, other than the desired antigen, that neither bind to an HLA allele nor activate an immune response. Antigen delivery systems can play crucial roles in improving cancer vaccines. The delivery systems can perform two critical functions, which the absence of currently limits the efficacy of cancer vaccines: promote targeting to dendritic cells (DCs) and facilitate cytosolic delivery. This proposal describes the development of an anthrax delivery system for delivering tumor antigens. My overarching hypothesis is that the anthrax machinery is well suited for delivering tumor antigens, because it can efficiently perform protein translocation. In nature, the delivery system transports toxins into the cell cytosol that rapidly induce cell death. The main components are easily modified for transporting non-native cargo into cells, including therapeutic peptides, proteins, and even small molecules. This proposal will develop the anthrax delivery system with two new features: to target dendritic cells and to deliver tumor antigens. These features will be developed to enhance tumor antigen activity in vivo (Aim 1) and to shed light on antigen processing and presentation (Aim 2). The impact of this work will extend beyond developing an effective tool for tumor antigen delivery. It will also facilitate the identification and study of tumor antigens selective for T cell activation, which will ultimately lead to the development of better tumor antigens for cancer vaccines in the clinic and beyond. The training plan and environment permits the design and study of the anthrax delivery system with the Pentelute lab (MIT), Irvine lab (Koch Institute for Integrative Cancer Research at MIT), and Wu lab (Dana- Farber Cancer Institute). The proposed studies will be performed with the equipment and resources available in these labs, and with the facilities available at the Swanson Biotechnology Center at the Koch Institute.

项目概要/摘要 癌症疫苗最近出现作为激活 T 细胞对抗癌症的选择性方法。治疗方法 基于称为肿瘤抗原的肽，源自肿瘤中具有免疫原性的肽序列。 另一类肿瘤抗原称为新抗原，由尚未检测到的肿瘤突变产生 通过免疫系统。这些含有肿瘤抗原或新抗原的癌症疫苗可以促进抗原特异性、 通过产生新的或放大现有的免疫反应，而不是非特异性的 T 细胞激活 对抗肿瘤。尽管这些治疗方法观察到了有希望的抗癌免疫反应，但有效的 选择性激活免疫系统仍然很困难。 一些挑战限制了癌症疫苗向临床的转化：(1) 癌症疫苗的充分吸收 抗原呈递细胞很难实现抗原，这极大地影响了肽是否有效 处理或呈递给 T 细胞。 (2) 肽的蛋白酶体加工难以预测，这可以 导致肽片段的形成，而不是所需的抗原，既不结合HLA等位基因，也不结合 激活免疫反应。抗原递送系统在改进癌症疫苗方面可以发挥至关重要的作用。这 输送系统可以执行两个关键功能，目前缺乏这两个功能限制了癌症的疗效 疫苗：促进针对树突状细胞 (DC) 的靶向并促进胞质递送。 该提案描述了用于递送肿瘤抗原的炭疽递送系统的开发。我的 最重要的假设是炭疽机制非常适合传递肿瘤抗原，因为它 可以有效地进行蛋白质易位。在自然界中，输送系统将毒素输送到细胞质中 迅速诱导细胞死亡。主要部件很容易修改，以便将非本地货物运输到 细胞，包括治疗性肽、蛋白质，甚至小分子。该提案将制定 炭疽递送系统具有两个新功能：靶向树突状细胞和递送肿瘤抗原。这些 将开发增强体内肿瘤抗原活性（目标 1）并阐明抗原的功能 处理和呈现（目标 2）。这项工作的影响将不仅仅限于开发有效的工具 用于肿瘤抗原递送。它还将有助于T细胞选择性肿瘤抗原的鉴定和研究 激活，这最终将导致在癌症疫苗中开发出更好的肿瘤抗原 诊所及其他。 培训计划和环境允许设计和研究炭疽输送系统 Pentelute 实验室（麻省理工学院）、尔湾实验室（麻省理工学院科赫综合癌症研究所）和 Wu 实验室（Dana- 法伯癌症研究所）。拟议的研究将利用现有的设备和资源进行 这些实验室以及科赫研究所斯旺森生物技术中心的设施。