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.

项目总结/摘要 癌症疫苗最近出现作为一种选择性的方式来激活T细胞对抗癌症。的治疗 基于称为肿瘤抗原的肽，其来源于具有免疫原性的肿瘤中的肽序列。 另一类肿瘤抗原，称为新抗原，产生于尚未检测到的肿瘤突变 免疫系统的影响。这些具有肿瘤抗原或新抗原的癌症疫苗可以促进抗原特异性， 而不是非特异性的T细胞激活，通过产生新的或放大现有的免疫反应， 对抗肿瘤尽管用这些治疗观察到有希望的抗癌免疫应答，但有效的免疫抑制剂仍然存在。 免疫系统的选择性激活仍然很困难。 几个挑战限制了癌症疫苗向临床的转化：（1）足够的肿瘤疫苗的摄取。 很难通过抗原呈递细胞获得抗原，这极大地影响了肽是否被 处理或呈递给T细胞。(2)蛋白酶体对肽的加工是难以预测的，这可以 导致形成除了所需抗原以外的肽片段，其既不结合HLA等位基因， 激活免疫反应抗原递送系统可以在改进癌症疫苗中发挥关键作用。的 递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：促进靶向树突状细胞（DC）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 最重要的假设是，炭疽机器非常适合于传递肿瘤抗原，因为它 能高效地进行蛋白质转位。在自然界中，传递系统将毒素转运到细胞胞质溶胶中 快速诱导细胞死亡主要部件很容易修改，用于将非本地货物运输到 细胞，包括治疗肽，蛋白质，甚至小分子。该提案将发展 炭疽传递系统具有两个新的特点：靶向树突状细胞和传递肿瘤抗原。这些 将开发特征以增强体内肿瘤抗原活性（目标1）并阐明抗原 处理和呈现（目标2）。这项工作的影响将超越开发一个有效的工具 用于肿瘤抗原递送。这也将有助于T细胞选择性肿瘤抗原的鉴定和研究 激活，这将最终导致开发更好的肿瘤抗原用于癌症疫苗， 诊所和超越 培训计划和环境允许设计和研究炭疽传播系统， Pentelute实验室（MIT）、Irvine实验室（MIT科赫综合癌症研究所）和Wu实验室（Dana- Farber癌症研究所）。拟议的研究将利用现有的设备和资源进行 在这些实验室，并与设施可在斯旺森生物技术中心在科赫研究所。