Chaperoning epitopes to induce protective T cell responses

陪伴表位诱导保护性 T 细胞反应

基本信息

批准号：
10648793
负责人：
Maxim Rosario
金额：
$ 24.56万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-01-20 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10648793
关键词：
Acids Adjuvant Animal Model Antigen Presentation Attention Biological Assay CD8-Positive T-Lymphocytes CD8B1 gene Cancer Vaccines Cells Cellular Immunity Clinical Coculture Techniques Communicable Diseases Cytosol Dendritic Cells Encapsulated Endosomes Epitopes FDA approved Flow Cytometry Goals HIV HIV-1 Human Papillomavirus Immune Immune response Immunity Immunotherapy In Vitro Interleukin-2 Malignant Neoplasms Malignant neoplasm of cervix uteri Measures Mediating Modeling Modernization Molecular Chaperones Mus Noise Oncoproteins Peptide Vaccines Peptides Physiologic pulse Plasmids Production Proliferating Protac Protein Binding Domain Proteolysis Proteolytic Processing Role Safety Signal Transduction Splenocyte Subunit Vaccines System T cell infiltration T cell response T-Cell Activation T-Lymphocyte Technology Testing Tumor Cell Line Tumor Specific Peptide Ubiquitin Vaccination Vaccine Adjuvant Vaccine Therapy Vaccines Validation Virus Virus Diseases cancer therapy chemical conjugate cytotoxic effector T cell experimental study immunogenicity improved in vivo evaluation knock-down mouse model multicatalytic endopeptidase complex nanoparticle neoantigens neutralizing antibody novel particle peptide based vaccine peptide vaccination preclinical efficacy prophylactic protein aminoacid sequence protein degradation recruit response secondary infection small molecule therapeutic nanoparticles tumor tumor eradication tumor growth ubiquitin-protein ligase vaccine development vaccine platform vaccine response vaccine strategy vaccinology

项目摘要

Project Summary CD8 T cell mediated immunity is instrumental in the clearance of numerous viruses and protection from secondary infections. With the advent of cancer vaccines and a better appreciation for the central role of cell mediated immunity, T cell responses are at the forefront of modern vaccinology. Synthetic Long Peptide (SLP) vaccination has proved effective in cervical cancer trials and we have shown that SLPs can be used to focus T cell responses in infectious disease. Despite their advantages and preclinical efficacy, SLPs must be formulated with sometimes toxic and expensive experimental adjuvants to induce immune responses. Furthermore, the immunogenicity of SLPs is hampered by the relatively poor delivery of soluble peptides to dendritic cells (DCs) and the suboptimal processing of SLPs by the ubiquitin-proteasome system (UPS) into short peptides that are then presented to CD8 T cells. Here, we propose to test an SLP-based vaccine composed of nanoparticles loaded with epitope specific SLPs modified with a proteolysis targeting molecule (ProTM) that recruits E3 ubiquitin ligase, thus optimizing SLP degradation via the UPS and subsequent presentation of SLP epitopes to T cells. We plan to synthesize, optimize, and test an SLP vaccine that utilizes biodegradable nanoparticles loaded with either a T cell-activating adjuvant or SLPs modified with an endosomal escaped domain (EED) and ProTM. We anticipate that our vaccine will elicit robust T cell responses by targeting both adjuvants and modified SLPs to DCs. Once internalized, SLP's will be released from the biodegradable particles, gain access to the cytosol, and be trafficked to the UPS for degradation, thus enhancing peptide presentation via MHCI to CD8 T cells. Our proposal describes a vaccine platform that can be easily tailored to treat malignancies or prophylactically to generate protective T cell responses against infectious disease. It is the first vaccine platform that utilizes ProTMs to enhance antigen presentation to T cells.

项目概要 CD8 T 细胞介导的免疫有助于清除多种病毒并防止感染继发感染。随着癌症疫苗的出现以及对细胞核心作用的更好认识 T 细胞反应介导的免疫处于现代疫苗学的前沿。合成长肽（SLP）疫苗接种在宫颈癌试验中已被证明是有效的，我们已经证明 SLP 可用于集中 T 传染病中的细胞反应。尽管 SLP 具有优势和临床前功效，但仍必须制定有时使用有毒且昂贵的实验佐剂来诱导免疫反应。此外， SLP 的免疫原性因可溶性肽向树突状细胞 (DC) 的递送相对较差而受到阻碍泛素蛋白酶体系统 (UPS) 将 SLP 加工成短肽的效果不佳然后呈递给 CD8 T 细胞。在这里，我们建议测试一种由纳米粒子组成的基于 SLP 的疫苗载有表位特异性 SLP，该 SLP 经蛋白水解靶向分子 (ProTM) 修饰，可招募 E3 泛素连接酶，从而通过 UPS 优化 SLP 降解以及随后将 SLP 表位呈递给 T 细胞。我们计划合成、优化和测试一种 SLP 疫苗，该疫苗利用负载有 T 细胞激活佐剂或用内体逃逸结构域 (EED) 和 ProTM 修饰的 SLP。我们预计我们的疫苗将通过靶向佐剂和修饰的 SLP 来引发强大的 T 细胞反应 DC。一旦内化，SLP 将从可生物降解的颗粒中释放出来，进入细胞质，并被运输到 UPS 进行降解，从而增强肽通过 MHCI 呈递给 CD8 T 细胞。我们的该提案描述了一个疫苗平台，可以轻松定制以治疗恶性肿瘤或预防性产生针对传染病的保护性 T 细胞反应。这是第一个利用 ProTM 增强 T 细胞的抗原呈递。