(Attack)2: Genetic engineering of cellular and humoral immunity to cure HIV

（攻击）2：细胞和体液免疫基因工程治愈艾滋病毒

基本信息

批准号：
9890819
负责人：
IRVIN S.Y. CHEN
金额：
$ 287.22万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-07 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9890819
关键词：
Ablation Address Adverse effects Animal Model Animals Antibody Formation Autologous B-Lymphocytes Berlin Biodistribution Biology Blood CCR5 gene Cell Transplantation Cells Cellular Immunity Cellular biology Clinical Research Clinical Trials Complement Development Differentiated Gene Disease Drug or chemical Tissue Distribution Elements Engineered Gene Engineering Engraftment Fred Hutchinson Cancer Research Center Gene Delivery Gene-Modified Genetic Genetic Engineering Grant HIV HIV-1 Hematopoietic stem cells Highly Active Antiretroviral Therapy Homologous Transplantation Human Humoral Immunities Immune Immunity Immunology Immunotherapeutic agent Immunotherapy Infant Infection Injections Lentivirus Vector London Macaca mulatta Malignant Neoplasms Mediating Modeling Neuraxis Patients Phase I/II Clinical Trial Phase I/II Trial Plasma Publishing Reagent Safety Site Stem cell transplant T cell therapy T-Lymphocyte Technology Testing Therapeutic Therapeutic Studies Tissues Transgenes Transplantation Treatment Efficacy Universities Variant Viral Viremia Virus Washington Work Yang adaptive immune response arm base cell behavior cellular engineering chimeric antigen receptor chimeric antigen receptor T cells chronic infection engineered T cells experience gene therapy gene transplantation for gene therapy humanized mouse immune function in vivo inhibitor/antagonist knock-down latent HIV reservoir neutralizing antibody nonhuman primate novel preclinical development programs response simian human immunodeficiency virus small hairpin RNA stem cell biology success targeted delivery therapeutic gene tumor vector

项目摘要

Overall: Project Summary/Abstract The hypothesis to be tested in our U19 Program Project is that combining therapies of gene-engineered cellular (chimeric antigen receptor (CAR)) and humoral (broadly neutralizing antibodies (bNAb)) immune reagents will lead to a cure of HIV-1 disease. In the single remarkable case of the “Berlin patient”, allogeneic transplant of CCR5Δ32 donor cells resulted in a functional cure without evidence for remaining HIV-1. However, a universal unresolved limitation of transplant of gene-engineered hematopoietic stem/progenitor cells (HSPC) has been the difficulty of achieving engraftment levels sufficient to provide good therapeutic efficacy. We propose here to focus on building gene-engineered cellular and humoral immune therapeutics. One approach is a CAR recognizing HIV-1 infected cells. T cell immunotherapy with tumor specific CARs delivered by adoptive T cell therapy has proven to be effective against cancer in early human studies. We hypothesize that HSPC based delivery of CAR- T cells can enhance the number and functional responses of the resultant engineered T cells. To complement the engineering of T cell-mediated immunity, we also propose to engineer B cells to express bNAbs modified as single chain variants (scFv-Fc bNAb). BNAbs directed to HIV-1 have shown promise at suppressing viremia in animal models and clearing SHIV from the blood and tissues of infant rhesus macaques and human clinical studies show effective suppression. Nonetheless, bNAbs require multiple injections to maintain levels required to suppress virus in plasma and have not cleared virus in chronic infection. We will use novel lentiviral vectors gene-engineered to target delivery of scFv-Fc bNAb into B cells in vivo without ex vivo manipulation. We hypothesize that this strategy will promote bNAb production, biodistribution and activation/differentiation of gene- modified B cells to clear HIV-1 reservoirs. Finally, success of these gene-modifying therapeutics depends upon achieving sufficient systemic levels of gene-modified cells. Thus, another project will specifically address means to modulate up or down the levels of gene-modified cells to achieve maximum therapeutic efficacy. In addition, should any adverse effects be observed, the same reagent can be used to quickly eliminate gene-modified cells, providing a “kill-switch”, and thus an added safety element to the overall approach. Drs. Kitchen and Chen (UCLA) will serve as dual-PIs. Both have extensive experience in general stem cell biology and its applications to HIV-1 disease. The Project/Core Leaders have expertise in HIV-1 biology and gene therapeutic approaches to HIV-1 disease. The breadth of expertise ranges from vector and transgene development (Chen, An, Morizono, Kitchen, Symonds), development and use of animal models for HSPC biology (Kitchen, An, Morizono, Chen, Kiem), anti-HIV-1 immune function (Yang, Kitchen), understanding of HSPC behavior (Chen) to clinical trial implementation (Symonds).

总体：项目摘要/摘要在我们的U19程序项目中要检验的假设是将基因工程细胞的疗法结合在一起（嵌合抗原受体（CAR））和体液（广泛中和抗体（BNAB））免疫试剂将导致治愈HIV-1疾病。在“柏林患者”的一个显着情况下，同种异体移植 CCR5Δ32供体细胞可产生功能性治疗，而没有证据表明剩余的HIV-1。但是，是通用基因工程造血茎/祖细胞（HSPC）的未解决的限制一直是难以实现足以提供良好治疗效率的植入水平。我们在这里建议集中精力建立基因工程的细胞和体液免疫疗法。一种方法是识别的汽车 HIV-1感染细胞。 T细胞免疫疗法用自适应T细胞疗法提供的肿瘤特异性汽车具有事实证明，在早期人类研究中对癌症有效。我们假设基于HSPC的CAR- T细胞可以增强所得工程T细胞的数量和功能响应。完成 T细胞介导的免疫力的工程，我们还建议设计B细胞以表达被修饰为BNABS 单链变体（SCFV-FC BNAB）。针对HIV-1的BNAB在抑制病毒血症中显示出希望动物模型和从婴儿恒河猕猴和人类临床的血液中清除SHIV 研究显示有效的抑制。但是，BNAB需要多次注射才能维持所需的水平抑制血浆中的病毒，尚未清除慢性感染中的病毒。我们将使用新颖的慢病毒载体基因工程技术是将SCFV-FC BNAB靶向递送在体内的B细胞中，而无需进行体内操作。我们假设该策略将促进基因的BNAB产生，生物分布和激活/分化修饰的B细胞清除HIV-1储层。最后，这些基因改良治疗剂的成功取决于达到足够的全身性基因修饰细胞。那，另一个项目将特别解决调节基因改性细胞的水平以达到最大的治疗效率。此外，如果观察到任何不良反应，则可以使用相同的试剂来快速消除基因修饰的细胞，即提供“杀伤开关”，从而为整体方法提供了更大的安全元素。博士。厨房和陈（UCLA）将用作双PI。两者在整个干细胞中都有丰富的经验生物学及其在HIV-1疾病中的应用。项目/核心领导者在HIV-1生物学方面具有专业知识，基因治疗方法用于HIV-1疾病。专业知识的广度范围从向量和转换开发（Chen，An，Morizono，Kitchen，Symonds），用于HSPC生物学动物模型的开发和使用（厨房，AN，Morizono，Chen，Kiem），抗HIV-1免疫功能（Yang，厨房），对HSPC的理解行为（陈）到临床试验实施（Symonds）。