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.

项目摘要 CD8 T细胞介导的免疫力有助于清除众多病毒和免受保护继发感染。随着癌症疫苗的出现，对细胞的核心作用更好地欣赏介导的免疫力，T细胞反应在现代疫苗学的最前沿。合成长肽（SLP）事实证明，疫苗接种在宫颈癌试验中有效，我们已经证明SLP可用于聚焦T 传染病的细胞反应。尽管具有优势和临床前的功效，但必须配制SLP 有时有毒且昂贵的实验佐剂可诱导免疫反应。此外， SLP的免疫原性受到可溶性肽向树突状细胞（DCS）的相对较差的递送而受到阻碍。以及通过泛素 - 蛋白酶体系统（UPS）对SLP的次优处理然后呈现给CD8 T细胞。在这里，我们建议测试由纳米颗粒组成的基于SLP的疫苗用蛋白水解靶向分子（Protm）修饰的表位特异性SLP，募集E3泛素连接酶，因此通过UPS和随后将SLP表位呈现给T细胞来优化SLP降解。我们计划合成，优化和测试SLP疫苗，该疫苗利用可生物降解的纳米颗粒加载用内体ESC的结构域（EED）和Protm修饰的T细胞激活佐剂或SLP。我们预计我们的疫苗将通过靶向佐剂和修饰的SLP来引起强大的T细胞反应 DCS。一旦内部化，SLP将从可生物降解的颗粒中释放出来，进入细胞质，然后被贩运到UPS进行降解，从而通过MHCI提高了肽表现为CD8 T细胞。我们的提案描述了一个疫苗平台，可以轻松量身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。这是第一个利用的疫苗平台原本以增强对T细胞的抗原表现。