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：
9322064
负责人：
STEVEN Grant DEEKS
金额：
$ 149.18万
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/9322064
关键词：
AIDS prevention Acute Adjuvant Adult Antibodies Antibody Response Antigens Antiviral Agents Awareness CD8-Positive T-Lymphocytes Cells Cervical Chronic Combined Vaccines Consensus Cytotoxic T-Lymphocyte-Associated Protein 4 DNA DNA Vaccines Defect Disease Disease remission Effector Cell Electroporation Environment Epitopes Exhibits Exposure to Generations Goals HIV HIV Infections HIV-1 Human Human Papilloma Virus Vaccine Human Papillomavirus Human papillomavirus 16 Immune Immune checkpoint inhibitor Immune response Immune signaling Immune system Immunosuppressive Agents Individual Infection Inflammation Interdisciplinary Study Interleukin-12 Intervention Lesion Life Malignant Neoplasms Measures Modeling Monoclonal Antibodies Mutation Outcome Pathway interactions Phenotype Pilot Projects Placebo Control Placebos Plasmids Population Premalignant Prospective Studies Proteins Randomized Randomized Clinical Trials Regimen SIV Safety Series T cell response T-Lymphocyte Testing Therapeutic Time Tissues Toxic effect Vaccination Vaccine Clinical Trial Vaccines Viral reservoir Virus Virus Diseases Woman Work antiretroviral therapy arm base cohort exhaust experience immunogenic immunogenicity improved innovation nonhuman primate novel novel strategies plasmid DNA programs response safety study success targeted treatment 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.

抽象的我们计划的核心前提是在缺乏抗逆转录病毒治疗的情况下持久控制艾滋病毒（“缓解”）需要从头产生有效且持续的 HIV 特异性 CD8+ 细胞反应，我们的计划受到 VGX-3100 (Inovio) 最近成功的启发，一种针对 HPV 的 DNA 治疗性疫苗，可导致人类癌前病变的组织病理学消退并且与 HPV 特异性 CD8+ T 细胞群的有效、持续增强密切相关。多进化枝 gag/pol/env DNA 疫苗（PENNVAX，Inovio）已被研究用于预防艾滋病毒，并且已知这种新方法的治疗潜力尚不清楚，并且将是未知的。然而，我们充分意识到，我们头两年的工作重点是DNA疫苗的管理。单独使用（PENNVAX-GP）不太可能足以实现已有疾病的缓解。已知在治疗艾滋病毒疾病期间持续存在的逃逸突变和免疫失调将阻碍疫苗的开发在头两年，我们将确定是否需要 IL- 的有效性和辅助方法。 12 可以增强这种疫苗的免疫原性这项工作是基于在非人类方面的丰富经验。在灵长类动物和未感染 HIV 的成年人中，IL-12 在 3 至 3 岁期间增强了 DNA 疫苗的免疫原性。 5、我们将确定使用 pembrolizumab (Merck) 阻断 PD-1 是否可以增强疫苗的有效性。可能将首次测试主动疫苗接种期间的 PD-1 阻断是否可以改善免疫广度我们的研究将利用我们的巨大优势。建立多学科研究团队，寻求高度创新的疫苗测量方法如果我们成功的话，我们将在该计划结束时得到一个结果。一种可行的疫苗策略，具有可控的安全性，并且已知具有高度免疫原性。