Comparison of Dendritic Cell-Based Therapeutic Vaccine Strategies for HIV Functional Cure

基于树突状细胞的 HIV 功能性治愈治疗疫苗策略的比较

基本信息

批准号：
10198701
负责人：
Bernard Jonas C Macatangay
金额：
$ 118.5万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-14 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10198701
关键词：
Acquired Immunodeficiency Syndrome Adverse event Advisory Committees Antigen-Presenting Cells Antigens Autologous Biological Assay Blood CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes Cell Maturation Cell Therapy Cells Cellular biology Clinical Research Clinical Trials DNA Data Dendritic Cell Vaccine Dendritic Cells Dinoprostone Disease remission Dose Double-Blind Method Epitopes Evaluation Frequencies Genetic Transcription Goals Growth HIV HIV Antigens HIV Infections HIV vaccine Immune Immune response Immune system Immunologic Markers Immunologics Immunology procedure Immunotherapy In Vitro Individual Interferon Type II Interferons Interleukin-1 beta Interleukin-6 Knowledge Laboratories Link Measures Modification Mosaicism Myeloid-derived suppressor cells Outcome Peptides Phase Phase I/II Trial Pilot Projects Placebos Plasma Play Poly I-C Preparation Proteome RNA Randomized Randomized Clinical Trials Regulatory T-Lymphocyte Reproducibility Reproducibility of Results Research Residual state Role Safety Scientist Seminal Specific qualifier value T-Lymphocyte TNF gene Techniques Testing Vaccination Vaccine Design Vaccine Therapy Vaccines Viremia Virus Virus Replication adaptive immune response antiretroviral therapy arm base cell type comparative design double-blind placebo controlled trial effector T cell efficacy evaluation efficacy outcomes follow-up immunogenic immunogenicity immunoregulation improved in vivo innovation insight novel response safety outcomes therapeutic vaccine therapeutically effective vaccine efficacy vaccine trial virology

项目摘要

PROJECT SUMMARY Dendritic cell (DC)-based therapeutic vaccines have shown the most promise for controlling HIV replication without antiretroviral therapy (ART). Although two seminal clinical trials demonstrated significant decreases in plasma viremia without ART that were associated with vaccine-induced HIV-specific immune responses, other DC-based vaccine studies have shown equivocal or no virologic efficacy. The disconnect between a DC-based vaccine's theoretical capability, supported by strong in vitro evidence of priming of effector T-cells, and the variable results of clinical trials, highlight important gaps in understanding the determinants of DC vaccine efficacy in vivo. We therefore propose a comparative analysis to confirm prior efficacy of DC vaccines and to test new, innovative DC vaccines with the dual goals of improving virological efficacy and identifying key determinants of DC vaccine efficacy. Specifically, we will conduct an initial phase I/II, randomized, double- blind, pilot study to compare safety and anti-HIV efficacy of four different DC-based vaccines and two corresponding placebos. The trial will evaluate two DC maturation techniques (the prostaglandin E2-matured DCs, which were partially effective in the two seminal clinical trials, and the alpha-type-1 DCs, which have shown improved antigen-presenting and T-cell priming function ex vivo), two HIV immunogens (whole, inactivated, autologous HIV that was partially effective in the two trials, and a pool of HIV peptides covering the most highly-conserved regions in Gag and Pol combined with epitopes known to be associated with control of viremia in untreated HIV-infected individuals), and two dosing strategies (3 vs 6 doses). The primary efficacy outcome will be change in the inducible HIV reservoir from pre-vaccination to 2 weeks after the final vaccine dose. We will also further evaluate the in vivo anti-HIV efficacy of the DC vaccines by performing an extensive analysis of vaccine-induced changes in virologic and immunologic parameters with the secondary goal of identifying immune correlates of vaccine-induced virologic responses. The parameters measured will include residual plasma viremia, the number and transcriptional activity of HIV-infected cells, CD8+ T-cell inhibition of autologous virus replication, the magnitude, breadth, and polyfunctionality of immune responses, and immunoregulatory responses including regulatory T-cells and myeloid-derived suppressor cells. We propose a second clinical trial to assess reproducibility of initial findings from the first trial and to assess the impact of further refinements of DC vaccine designs on efficacy. We have developed pre-specified Go/No-Go criteria for moving forward to a second trial. The decision whether a specific DC vaccine will be evaluated in the second trial will be based on the primary and secondary virologic and immunologic endpoints of the first trial. This innovative, sequential, and iterative approach will evaluate multiple DC vaccines, elucidate determinants of vaccine efficacy, identify immune correlates of vaccine-induced reductions in HIV reservoirs, and provide new insights into the potential for DC vaccines to achieve durable HIV remission without ART.

项目摘要基于树突状细胞（DC）的治疗疫苗已显示出控制HIV复制的最有望没有抗逆转录病毒疗法（ART）。尽管两项开创性临床试验显示出显着下降与疫苗诱导的HIV特异性免疫反应相关的没有ART的血浆病毒血症，其他基于直流的疫苗研究表明模棱两可或没有病毒学功效。基于DC的断开连接疫苗的理论能力，得到了强烈的体外证据，证明了效应t细胞的启动和临床试验的可变结果突出了了解DC疫苗的决定因素的重要差距体内功效。因此，我们提出了比较分析，以确认直流疫苗的事先疗效和测试新的创新DC疫苗，其双重目标是提高病毒学功效并确定关键直流疫苗功效的决定因素。具体而言，我们将进行初始I/II期，随机，双重 - 盲人，试点研究，以比较四种不同DC疫苗的安全性和抗HIV功效相应的安慰剂。该试验将评估两种直流成熟技术（前列腺素E2成熟 DC在两个开创性临床试验中部分有效，并且具有具有α型DC的DC 显示了改善的抗原呈递和T细胞启动函数在体内），两种HIV免疫原（整个，在两项试验中灭活的自体HIV，以及覆盖艾滋病毒肽的一池 GAG和POL中最高度保存的区域与已知与控制有关的表位相结合未经治疗的艾滋病毒感染者的病毒血症）和两种剂量策略（3剂6剂量）。主要功效结果将是可诱导的HIV储层从疫苗接种到最终疫苗后2周的变化剂量。我们还将进一步评估DC疫苗的体内抗HIV疗效分析疫苗诱导的病毒学和免疫学参数变化的次要目标鉴定疫苗诱导的病毒学反应的免疫相关性。测得的参数包括残留血浆病毒血症，HIV感染细胞的数量和转录活性，CD8+ T细胞抑制自体病毒复制，免疫反应的大小，广度和多功能性，以及免疫调节反应，包括调节性T细胞和髓样衍生的抑制细胞。我们提出了一个第二次临床试验，以评估第一次试验中初始发现的可重复性，并评估 DC疫苗设计的进一步改进。我们已经开发了预先指定的GO/NO-GO标准前进到第二次审判。是否将在第二次评估特定的直流疫苗的决定试验将基于第一个试验的主要和次要病毒学和免疫学终点。这创新，顺序和迭代方法将评估多种DC疫苗，阐明的决定因素疫苗功效，确定疫苗诱导的HIV储层降低的免疫相关性，并提供新的深入了解DC疫苗在没有ART的情况下实现持久HIV的潜力。