Therapeutic vaccination and PD-1 blockade in treated HIV disease

治疗性疫苗接种和 PD-1 阻断治疗 HIV 疾病

基本信息

批准号：
9902324
负责人：
STEVEN Grant DEEKS
金额：
$ 137.73万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
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：
2017-04-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9902324
关键词：
AIDS prevention Acute Adjuvant Adult Antibodies Antibody Response Antigens Antiviral Agents Awareness CD8-Positive T-Lymphocytes CTLA4 gene Cells Cervical Chronic Combined Vaccines Consensus DNA DNA Vaccines DNA delivery Defect Disease Disease remission Effector Cell Electroporation Environment Epitopes Exhibits Exposure to Generations Goals HIV HIV Infections HIV vaccine HIV-1 Human Human Papillomavirus Human papillomavirus 16 Immune Immune System Diseases Immune checkpoint inhibitor Immune response Immune signaling Immune system Individual Infection Inflammation Interdisciplinary Study Interleukin-12 Intervention Lesion Life Malignant Neoplasms Measures Modeling Monoclonal Antibodies Mutation Nivolumab Outcome PD-1 blockade Pathway interactions Phenotype Pilot Projects Placebos Plasmids Population Prospective Studies Proteins Randomized Clinical Trials Regimen SIV Safety Safety Management Series T cell response T-Lymphocyte Testing Therapeutic Time Tissues Toxic effect Vaccination Vaccine Clinical Trial Vaccine Therapy Vaccines Viral reservoir Virus Virus Diseases Woman Work anti-PD-1 anti-PD1 antibodies antiretroviral therapy arm base cohort exhaust experience immunogenic immunogenicity improved innovation nonhuman primate novel novel strategies plasmid DNA premalignant programmed cell death protein 1 programs randomized placebo-controlled clinical trial response safety study success targeted treatment therapeutic DNA therapeutic HPV vaccine therapeutic vaccine vaccine effectiveness vaccine efficacy vector vaccine virology

项目摘要

ABSTRACT The central premise of our program is that durable control of HIV in the absence of antiretroviral therapy (“remission”) will require the generation of de novo potent and sustained HIV-specific CD8+ cell responses that target evolutionarily conserved epitopes. Our program is inspired by the recent success of VGX-3100 (Inovio), a DNA therapeutic vaccine for HPV that leads to histopathologic regression of pre-malignant lesions in people and is associated with a potent, sustained boost to HPV-specific CD8+ T cell populations. A closely related multi-clade gag/pol/env DNA vaccine (PENNVAX, Inovio) has been studied for HIV prevention and is known to be both safe and highly immunogenic. The therapeutic potential of this novel approach is unknown and will be the focus of our work in the first two years. We are fully aware, however, that administration of a DNA vaccine alone (PENNVAX-GP) will unlikely be sufficient to achieve a disease remission. The presence of pre-existing escape mutations and immune dysregulation known to persist during treated HIV disease will hamper vaccine effectiveness, and adjuvant approaches will be likely be needed. In the first two years, we will determine if IL- 12 can enhance immunogenicity of this vaccine. This work is based on extensive experience in non-human primates and in HIV-uninfected adults showing IL-12 enhances immunogenicity of DNA vaccines. In Years 3 to 5, we will determine if PD-1 blockade with pembrolizumab (Merck) enhances vaccine effectiveness. This study will likely test for the first time if PD-1 blockade during active vaccination improves the breadth of the immune response and increases the numbers of effector cells. Our study will leverage the considerable strengths of our established multi-disciplinary research team to pursue highly innovative approaches to measuring vaccine immunogenicity and the viral reservoir. Should we be successful, we will have at the end of this program a viable vaccine strategy that has a manageable safety profile and is known to be highly immunogenic.

抽象的我们计划的主要前提是，在没有抗逆转录病毒疗法的情况下，对HIV的持久控制（“缓解”）将需要从头产生从头产生和持续的HIV特异性CD8+细胞反应目标进化构成表位。我们的计划的灵感来自VGX-3100（Inovio）的成功启发，用于HPV的DNA治疗疫苗，导致人体恶性病变的组织病理学回归并且与HPV特异性CD8+ T细胞种群的潜力，持续增强有关。密切相关多层GAG/POL/ENV DNA疫苗（Pennvax，Inovio）已用于预防HIV，已知已知既安全又高度免疫原性。这种新颖方法的治疗潜力是未知的，将是我们最初两年的工作重点。但是，我们完全意识到DNA疫苗的给药单独的（Pennvax-GP）不足以实现疾病的缓解。现有的存在逃避突变和已知在治疗的HIV疾病期间持续存在的免疫失调会阻碍疫苗有效性和调整方法可能需要。在最初的两年中，我们将确定是否il- 12可以增强该疫苗的免疫原性。这项工作基于非人类的丰富经验灵长类动物和艾滋病毒未感染的成年人在显示IL-12的成年人中增强了DNA疫苗的免疫原性。在第3年至 5，我们将确定使用pembrolizumab（Merck）阻断PD-1是否会提高疫苗的有效性。这项研究如果主动疫苗期间的PD-1封锁改善免疫的宽度，可能会首次测试响应并增加效应细胞的数量。我们的研究将利用我们的考虑优势建立的多学科研究团队，以追求高度创新的方法来测量疫苗免疫原性和病毒储量。如果我们成功，我们将在该计划的结尾可行的疫苗策略，具有可管理的安全性，并且已知具有高度免疫原性。