Therapeutic vaccination and PD-1 blockade in treated HIV disease

摘要 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， 靶向进化上保守的表位。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、持续增强有关。密切相关的一个 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 既安全又具有高免疫原性。这种新方法的治疗潜力尚不清楚，并将 我们前两年的工作重点。然而，我们充分意识到，DNA 疫苗的施用 单独使用（PENNVAX-GP）不太可能足以实现疾病缓解。预先存在的存在 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 有效性，并且可能需要辅助方法。在头两年，我们将确定 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 灵长类动物和未感染 HIV 的成年人中显示 IL-12 增强了 DNA 疫苗的免疫原性。第 3 年至 5，我们将确定使用 pembrolizumab (Merck) 阻断 PD-1 是否可以增强疫苗有效性。这项研究 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 反应并增加效应细胞的数量。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 免疫原性和病毒库。如果我们成功的话，我们将在该计划结束时得到 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。

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.