Characterizing the therapeutic efficacy of CD8 T cell responses induced by the IL-15 superagonist ALT-803

表征 IL-15 超级激动剂 ALT-803 诱导的 CD8 T 细胞反应的治疗效果

基本信息

批准号：
10529269
负责人：
SHELBY L OCONNOR
金额：
$ 75.5万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-12-05 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10529269
关键词：
Alleles Animals Anti-Retroviral Agents Antigens Antiviral Agents CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes Cell physiology Cells Cellular Immunity Characteristics Clinical Trials Coupled Data Development Effector Cell Epitopes Exhibits Foundations Funding Gene Expression Profile Grant HIV HIV vaccine Human Immune response Immunocompetent Immunotherapeutic agent Immunotherapy Individual Infection Infection Control Infection prevention Interleukin-15 Intervention Location Macaca Macaca fascicularis Macaca mulatta Malignant Neoplasms Manuscripts Mediating Memory Modeling Monkeys Mutation Oral Pathway interactions Pharmaceutical Preparations Phenotype Plasma Play Population Preventative vaccination Preventive vaccine Publishing Reagent Role SIV Signal Transduction T cell response T-Cell Immunologic Specificity T-Lymphocyte Testing Therapeutic Treatment Efficacy Vaccinated Vaccination Vaccine Research Vaccines Viral Viral Physiology Viremia Virus Virus Diseases Virus Replication anti-cancer anti-viral efficacy antiretroviral therapy clinically relevant cytokine design effective intervention immune modulating agents immunogenic immunoregulation lymph nodes nonhuman primate pathogen posters pre-clinical prophylactic recruit response therapeutic vaccine tumor universal vaccine vector vaccine

项目摘要

PROJECT SUMMARY We do not have a vaccine or a cure for HIV. CD8 T cells are necessary for initial control of HIV viremia, but attempts to design a CD8 T cell based HIV vaccine have been met with challenges. These include (1) eliciting cellular immune responses against the most immunogenic regions of HIV and (2) enhancing the function of antiviral immune responses at the right location to contain virus replication. This proposal is a renewal of our original R01 testing the hypothesis that CD8 T cells targeting invariant epitopes are unable to detect and destroy virally-infected cells. Based on the data generated during the grant period, we published 4 manuscripts, presented 4 oral abstracts, presented 7 poster abstracts, and delivered 8 seminars. We found that SIV control was delayed and incomplete in the absence of CD8 T cells targeting the most immunogenic regions of SIV. Without detecting effective CD8 T cells to suppress SIV replication in animals with non-protective MHC alleles, our study raises questions over the feasibility of designing a universal vaccine to elicit CD8 T cells targeting invariant epitopes. During the last grant period and using funds from the previous R01, we also made the remarkable observation that the immunomodulatory IL-15 superagonist ALT-803 could boost CD8 T cell function to promote virus suppression in macaques that received prior vaccination, but not in vaccine-naïve animals. The data gathered from these studies has laid the foundation for us to test the hypothesis that that ALT-803 treatment enhances the antiviral function of vaccine-elicited memory CD8 T cells by recruiting IL-15 responsive antigen-specific CD8 T cells to lymph nodes to kill infected target cells. We will test this hypothesis by comparing ALT-803 mediated suppression of SIV in vaccine- naïve and vaccinated macaques. We also propose to characterize the responding CD8 T cell population to determine if ALT-803 enhanced memory CD8 T cells in the vaccinated animals exhibit increased antiviral function that is associated with transcription signatures indicative of increased IL-15 signaling through the JAK/STAT pathway. Together these data will help identify the features of functionally relevant antiviral CD8 T cells in animals with non-protective MHC alleles. Our study is relevant because ALT-803 is being used in clinical trials as an anti-tumor and anti-viral agent. We want to maximize the effect of ALT-803 so that it is used most effectively in these settings. Certain studies of ALT-803 cannot be performed in humans, including the one that we have proposed. We will specifically evaluate whether vaccination BEFORE SIV infection is necessary for ALT-803 to elicit functionally active CD8 T cells AFTER SIV infection. This is a paradigm shifting approach for vaccine research, because it places a value on prophylactic vaccination of immunocompetent individuals so that interventions are effective in HIV+ immunocomprimised individuals.

项目摘要我们没有真空或治愈艾滋病毒的治疗方法。 CD8 T细胞对于初始控制HIV病毒血症是必需的，但是，试图设计基于CD8 T细胞的HIV疫苗的尝试已面临挑战。这些包括（1）引起针对HIV最免疫原性区域的细胞免疫复杂，（2）增强抗病毒免疫反应在正确位置包含病毒复制的功能。该建议是我们原始R01的续签表位无法检测和破坏几乎感染的细胞。基于在我们发表了4个手稿，介绍了4个口头摘要，介绍了7个海报摘要，并且交付了8个半手。我们发现，在没有CD8 T的情况下，SIV控制被延迟和不完整针对SIV最免疫原性区域的细胞。没有检测到有效的CD8 T细胞抑制具有非保护MHC等位基因的动物的SIV复制，我们的研究提出了问题设计通用疫苗以引起靶向不变表位的CD8 T细胞的可行性。在上一个赠款期间，并使用上一个R01的资金，我们也做出了非凡的观察到免疫调节的IL-15超级飞机ALT-803可以将CD8 T细胞功能提高到促进接受先前接种疫苗的猕猴抑制病毒，但未在疫苗中抑制动物。从这些研究中收集的数据为我们测试了以下假设的基础 ALT-803处理增强了疫苗吸收记忆CD8 T细胞的抗病毒功能通过募集IL-15反应式抗原特异性CD8 T细胞以杀死受感染靶标的淋巴结细胞。我们将通过比较Alt-803介导的SIV抑制在疫苗中的抑制来检验这一假设。幼稚的猕猴。我们还建议表征响应的CD8 T细胞人口确定ALT-803是否增强了接种动物中的记忆CD8 T细胞与转录特征相关的抗病毒功能的增加，表明IL-15增加通过JAK/STAT途径发出信号。这些数据一起将有助于确定具有非保护MHC等位基因的动物中与功能相关的抗病毒CD8 T细胞。我们的研究很重要，因为ALT-803在临床试验中用作抗肿瘤和抗病毒代理人。我们希望最大化ALT-803的效果，以便在这些设置中最有效地使用它。某些对ALT-803的研究不能在人类中进行，包括我们提出的研究。我们将特别评估Alt-803是否需要在SIV感染之前进行疫苗接种在SIV感染后引起功能活性的CD8 T细胞。这是一种范式转移方法疫苗研究，因为它具有免疫能力的预防性疫苗的价值个体，以便干预措施在HIV+免疫光生的个体中有效。