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.

项目摘要 细胞毒性T淋巴细胞（CTL）介导的免疫反应是主要的效应器机制 针对癌症和病毒感染的免疫疗法。疫苗能够提高CTL的反应，并且正在 在实验室和临床环境中进行密切追求。但是，疫苗之间存在很大差距 这些疫苗的开发工作和功效。这个差距激发了我们重新检查当前疫苗接种 策略并制定缩小差距的替代策略。当前的策略依赖于树枝内 疫苗的细胞（DC）加工，由于该过程中嵌入了多个屏障，因此该疫苗不有效。我们 因此，旨在制定独特的疫苗接种策略，该策略完全绕过DC内部处理。对此 结束，并基于我们的初步研究结果 基于多肽（ITEP）的融合作为疫苗载体，能够直接加载CTL表位（CTL疫苗） 在直流表面上的MHC I类配合物上。这些表位随后将被DC用于诱导 CTL响应。我们假设融合将大大提高疫苗的有效性 与需要DC内处理的疫苗相比。我们将设计并表征与 以下两个目的：目标1：检查体外ABD-PMMP- ePitope融合的功能。目标2： 在体内建立ABD-PMMP - ePitope融合的功能和效果。 考虑到CTL疫苗的重要性和当前挑战，这是主要贡献 拟议的研究是，它探索了一种新颖和直接的表位加载策略，以前所未有地加强 CTL疫苗诱导的反应。这种小说但直截了当的策略可能会带来前所未有的 对这些疫苗的影响，使它们能够在免疫疗法和免疫中起更具决定性的作用 癌症，感染和其他疾病的预防。