Enhancing cytotoxic T lymphocyte (CTL) responses by directly loading CTL epitope vaccines onto MHC Class I complexes on the dendritic cell surface

通过将 CTL 表位疫苗直接负载到树突状细胞表面的 MHC I 类复合物上，增强细胞毒性 T 淋巴细胞 (CTL) 反应

• 批准号: 9299648
• 负责人: Mingnan Chen
• 金额: $ 18.92万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9299648
• 关键词: Albumins; Binding; Bypass; Cancer Vaccines; Cell surface; Cells; Clinical; Complex; Cytotoxic T-Lymphocytes; Data; Defense Mechanisms; Dendritic Cells; Disease; Elastin; Elements; Engineering; Epitopes; Gelatinase A; Immune; Immune response; Immunotherapy; In Vitro; Infection; Infection prevention; Laboratories; Lymph; Lymphocyte; Lymphocyte Activation; MHC Class I Genes; Malignant Neoplasms; Matrix Metalloproteinases; Mediating; Methods; Modeling; Mus; Organ; Patients; Peptides; Play; Process; Production; Recruitment Activity; Research; Role; Spleen; Testing; Therapeutic; Therapeutic Effect; Vaccination; Vaccine Clinical Trial; Vaccines; Viral Cancer; Virus Diseases; base; cancer prevention; design; improved; in vivo; lymph nodes; macromolecule; melanoma; novel; novel vaccines; patient population; polypeptide; prophylactic; public health relevance; response; vaccination strategy; vaccine delivery; vaccine development; vaccine effectiveness; vaccine efficacy

Project summary Cytotoxic T lymphocyte (CTL)-mediated immune responses are the primary effector mechanism in immunotherapies against cancer and virus infection. Vaccines are able to boost CTL responses, and are being intensively pursued in the laboratory and clinical settings. However, there is a large gap between the vaccine development effort and the efficacy of these vaccines. This gap motivates us to reexamine current vaccination strategies and to develop an alternative strategy to close the gap. Current strategies rely on the intra-dendritic cell (DC) processing of vaccines, which is not efficient due to multiple barriers embedded in the process. We thus aim to develop a distinct vaccination strategy that completely bypasses the intra-DC processing. To this end, and based on our preliminary research results, we propose to develop an immune-tolerant elastin-like polypeptide (iTEP)-based fusion as a vaccine carrier that is able to directly load CTL epitopes (CTL vaccines) onto the MHC class I complexes on DC surfaces. These epitopes will be subsequently used by DCs to induce CTL responses. We hypothesize that the fusion will drastically boost the effectiveness of the vaccines as compared to vaccines requiring intra-DC processing. We will engineer and characterize the fusion with the following two aims: Aim 1: Examine functionalities of the ABD-iTEP-pMMP-epitope fusion in vitro. Aim 2: Establish functionalities and effects of the ABD-iTEP-pMMP-epitope fusion in vivo. In consideration of the importance and current challenges of CTL vaccines, the main contribution of this proposed study is that it explores a novel and a direct epitope loading strategy to unprecedentedly strengthen CTL vaccine-induced responses. This novel yet straightforward strategy may bring about an unprecedented impact on these vaccines, allowing them to play a more decisive role in the immunotherapy and immune preventions of cancer, infections, and other diseases.

项目概要 细胞毒性T淋巴细胞（CTL）介导的免疫反应是主要效应机制 针对癌症和病毒感染的免疫疗法。疫苗能够增强 CTL 反应，并且正在开发中 在实验室和临床环境中得到深入研究。但与疫苗相比还有很大差距 这些疫苗的开发工作和功效。这一差距促使我们重新审视当前的疫苗接种 战略并制定替代战略来缩小差距。目前的策略依赖于树突内 疫苗的细胞（DC）加工，由于过程中存在多重障碍，效率不高。我们 因此，我们的目标是开发一种独特的疫苗接种策略，完全绕过 DC 内的处理。对此 最后，根据我们的初步研究结果，我们建议开发一种免疫耐受的类弹性蛋白 基于多肽（iTEP）的融合作为疫苗载体，能够直接负载CTL表位（CTL疫苗） 到 DC 表面上的 MHC I 类复合物上。这些表位随后将被 DC 用于诱导 CTL 响应。我们假设融合将极大地提高疫苗的有效性 与需要 DC 内处理的疫苗相比。我们将设计并表征与 以下两个目标： 目标 1：在体外检查 ABD-iTEP-pMMP-表位融合的功能。目标 2： 建立体内 ABD-iTEP-pMMP-表位融合的功能和效果。 考虑到CTL疫苗的重要性和当前的挑战，该研究的主要贡献 拟议的研究是探索一种新颖的直接表位加载策略来前所未有地加强 CTL 疫苗诱导的反应。这种新颖而直接的策略可能会带来前所未有的 对这些疫苗的影响，使其在免疫治疗和免疫中发挥更决定性的作用 预防癌症、感染和其他疾病。