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: 10297830
• 负责人: Nicholas L Truex
• 金额: $ 4.76万
• 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 2022-08-12
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10297830
• 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; anti-cancer; antibody engineering; anticancer research; base; cancer immunotherapy; cell type; design; immune activation; immunogenic; improved; in vivo; lethal factor; 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.

项目摘要/摘要 癌症疫苗最近成为激活T细胞针对癌症的选择性方法。治疗 基于被称为肿瘤抗原的肽，这些肽是源自免疫原性肿瘤中肽序列​​的。 另一种称为新抗原的肿瘤抗原是由尚未检测到的肿瘤突变引起的 通过免疫系统。这些用肿瘤抗原或新抗原的癌症疫苗可以促进抗原特异性， 而不是通过生成新的或放大现有免疫反应的非特异性T细胞激活 反对肿瘤。尽管通过这些治疗观察到有希望的抗癌免疫反应，但有效 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诊所的转化：（1）足够的吸收 抗原呈递细胞的抗原难以实现，这极大地影响了肽是否是 处理或呈现给T细胞。 （2）难以预测肽的蛋白酶体加工，哪个可以 导致肽片段的形成，除了所需的抗原以外，既不结合HLA等位基因也不结合 激活免疫反应。抗原递送系统可以在改善癌症疫苗中起关键作用。这 输送系统可以执行两个关键功能，目前缺乏限制癌症的功效 疫苗：促进靶向树突状细胞（DC）并促进胞质递送。 该建议描述了用于递送肿瘤抗原的炭疽递送系统的发展。我的 总体假设是炭疽机械非常适合输送肿瘤抗原，因为它 可以有效地执行蛋白质易位。在本质上，递送系统将毒素传输到细胞细胞质中 这会迅速诱导细胞死亡。主要组件很容易修改以将非本地货物运输到 细胞，包括治疗性肽，蛋白质，甚至是小分子。该建议将发展 具有两个新特征的炭疽递送系统：靶向树突状细胞并输送肿瘤抗原。这些 将开发特征以增强体内肿瘤抗原活性（AIM 1）并阐明抗原 处理和演示（目标2）。这项工作的影响将不仅仅是开发有效的工具 用于肿瘤抗原递送。它还将促进对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更好的肿瘤抗原 诊所及以后。 培训计划和环境允许使用 Pentelute Lab（MIT），Irvine Lab（MIT的Koch综合癌症研究所）和Wu Lab（Dana- 法伯癌研究所）。拟议的研究将使用可用的设备和资源进行 在这些实验室中，以及Koch Institute的Swanson Biotechnology Center提供的设施。

项目成果

Palladium-Mediated Incorporation of Carboranes into Small Molecules, Peptides, and Proteins.

• DOI: 10.1021/jacs.2c01932
• 发表时间: 2022-05-04
• 期刊: Journal of the American Chemical Society
• 影响因子: 15
• 作者: Gazvoda M;Dhanjee HH;Rodriguez J;Brown JS;Farquhar CE;Truex NL;Loas A;Buchwald SL;Pentelute BL
• 通讯作者: Pentelute BL

Anthrax Protective Antigen Retargeted with Single-Chain Variable Fragments Delivers Enzymes to Pancreatic Cancer Cells.

• DOI: 10.1002/cbic.202000201
• 发表时间: 2020-10-01
• 期刊: Chembiochem : a European journal of chemical biology
• 作者: Loftis AR;Santos MS;Truex NL;Biancucci M;Satchell KJF;Pentelute BL
• 通讯作者: Pentelute BL

Targeting Cancer Gene Dependencies with Anthrax-Mediated Delivery of Peptide Nucleic Acids.

• DOI: 10.1021/acschembio.9b01027
• 发表时间: 2020-06-19
• 期刊: ACS chemical biology
• 影响因子: 4
• 作者: Lu Z;Paolella BR;Truex NL;Loftis AR;Liao X;Rabideau AE;Brown MS;Busanovich J;Beroukhim R;Pentelute BL
• 通讯作者: Pentelute BL