Development of Allogeneic CAR T Cell Therapy for a Functional Cure of HIV Infection

开发同种异体 CAR T 细胞疗法以功能性治愈 HIV 感染

基本信息

批准号：
10581704
负责人：
TODD M ALLEN
金额：
$ 47.16万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-03-01 至 2027-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10581704
关键词：
Acceleration Allogenic Anti-Retroviral Agents Autologous B-Cell Acute Lymphoblastic Leukemia Berlin Binding CAR T cell therapy CCR5 gene CD19 gene CD28 gene CD8-Positive T-Lymphocytes Cardiovascular Diseases Cells Cellular biology Cellular immunotherapy Characteristics Chronic Clinical Clinical Trials Consumption Cytomegalovirus DNA Data Development Disease Disease Progression Disease remission Exhibits Functional disorder Generations Genes Genetic HIV HIV Infections HIV vaccine Head Hematopoietic Neoplasms Heterogeneity Human Immune Immune response Immune system Immunotherapeutic agent Immunotherapy Individual Infection Inflammation Infusion procedures Interruption Junk DNA Knowledge London Macaca mulatta Malignant Neoplasms Mediating Modification Morbidity - disease rate Pathogenesis Pathogenicity Patients Pharmaceutical Preparations Phenotype Production Resistance SIV Source T cell response T-Cell Development T-Lymphocyte Testing Therapeutic Time Tissues Vaccination Variant Viral Viral Load result Viral reservoir Virus allotransplant anti-viral efficacy antiretroviral therapy base editing cancer immunotherapy chimeric antigen receptor chimeric antigen receptor T cells chronic infection cost efficacy study engineered T cells human disease humanized mouse improved in vivo interest manufacturing cost mortality mouse model novel prevent prophylactic response stem cells success transcriptomics tumor vector induced vector-based vaccine viral rebound

项目摘要

Abstract: Antiretroviral therapy (ART) dramatically reduces HIV-associated morbidity and mortality (1). However, it is not a practical cure as eradication of HIV through ART alone is estimated to require over 60 years of treatment (1, 2). Numerous studies support that HIV-specific T cell responses are critical for efficient targeting and elimination of HIV infected cells that are the source of chronic infection (3-10). Unfortunately, viral escape and a limited presence of functional virus-specific effector CD8+ T cells undermine the potency of these responses in chronically infected individuals (11-17). As such, there is growing interest in the development of novel immunotherapeutic approaches to target and eliminate HIV-infected cells to achieve viral suppression in the absence of ART, a “functional cure”. Chimeric antigen receptor (CAR) T cell immunotherapies have demonstrated great promise against blood cancers (18-20), and now also demonstrate the potential to mitigate HIV/SIV infection in rhesus macaques (21, 22) and humanized mice (23-28). We recently showed that HIV-specific Dual CD4-based CAR T cells co- expressing independent 4-1BB and CD28 costimulatory domains restrict HIV replication and reduce viral burden in humanized mice (23). However, current limitations of using autologous T cells to derive CAR T cell products (TCPs), including time-consuming and costly manufacturing, insufficient or dysfunctional patient-derived T cells, and the inter-patient heterogeneity of TCPs, are barriers to their widespread application to human diseases. Development of allogeneic TCPs derived from healthy human donors, could, however, provide an ‘off-the-shelf’ treatment option to overcome these hurdles, as well as accelerate the use of CAR T cell therapies (29-38). Unfortunately, post-infusion elimination by the recipient’s immune system remains a major hurdle (39-41). Here we propose to leverage our expertise in CAR T cell biology (21, 23, 25, 26, 42, 43), base editing (44-49), and a humanized mouse model of HIV infection (50-58) to develop an allogeneic CAR T cell therapy against HIV. Building on our preliminary data applying efficient multiplex base editing to CAR T cells, we hypothesize that both base editing approaches and identification of an optimal allogenic donor will enable the development of an allorejection-resistant CD4-based CAR TCP with enhanced efficacy to eliminate HIV-infected cells and suppress HIV in the absence of ART. To test this hypothesis, we propose the following specific aims: Aim 1: Determine whether genetic modifications to allogeneic T cells can augment their in vivo persistence. Aim 2: Identify characteristics of allogeneic HIV-specific CD4CAR T cells that associate with enhanced persistence and antiviral efficacy. Aim 3: Compare the in vivo HIV efficacy of allogeneic versus autologous HIV-specific CD4CAR T cells, incorporating Aim 1 and 2’s signatures of improved allogeneic functionality.

摘要：抗逆转录病毒治疗 (ART) 可显着降低 HIV 相关发病率和死亡率 (1)。然而，这并不是一种实际的治愈方法，因为仅通过 ART 根除 HIV 估计需要 60 多年的时间大量研究支持 HIV 特异性 T 细胞反应对于有效靶向至关重要。并消除作为慢性感染源的 HIV 感染细胞 (3-10)。功能性病毒特异性效应 CD8+ T 细胞的有限存在破坏了这些细胞的效力慢性感染者的反应 (11-17) 因此，人们对发展的兴趣越来越浓厚。靶向并消除 HIV 感染细胞以实现病毒感染的新型免疫治疗方法在没有 ART 的情况下进行抑制，这是一种“功能性治愈”。嵌合抗原受体 (CAR) T 细胞免疫疗法已被证明具有巨大的前景血癌 (18-20)，现在还展示了减轻恒河猴 HIV/SIV 感染的潜力 (21, 22) 和人源化小鼠 (23-28) 我们最近表明，HIV 特异性双 CD4 CAR T 细胞共同作用。表达独立的 4-1BB 和 CD28 共刺激结构域限制 HIV 复制并减少病毒负荷然而，目前使用自体 T 细胞衍生 CAR T 细胞产品的局限性。 (TCP)，包括耗时且成本高昂的制造、患者来源的 T 细胞不足或功能失调， TCPs 的患者间异质性是其广泛应用于人类疾病的障碍。然而，开发来自健康人类捐赠者的同种异体 TCP，可以提供“现成的” 克服这些障碍并加速 CAR T 细胞疗法的使用的治疗方案 (29-38)。不幸的是，输注后接受者免疫系统的消除仍然是一个主要障碍 (39-41)。在这里，我们建议利用我们在 CAR T 细胞生物学 (21, 23, 25, 26, 42, 43)、碱基编辑方面的专业知识 (44-49) 和 HIV 感染人源化小鼠模型 (50-58) 开发同种异体 CAR T 细胞疗法基于我们对 CAR T 细胞应用多重碱基编辑的初步数据，我们促进碱基最佳编辑方法和同种异体供体的鉴定将使开发基于 CD4 的抗同种异体排斥 CAR TCP，增强消除 HIV 感染的功效为了检验这一假设，我们提出以下具体目标：目标 1：确定对同种异体 T 细胞进行基因修饰是否可以增强其体内活性坚持。目标 2：确定与增强型 HIV 特异性 CD4CAR T 细胞相关的特征持久性和抗病毒功效。目标 3：比较同种异体与自体 HIV 特异性 CD4CAR T 细胞的体内 HIV 功效，结合目标 1 和 2 的改进同种异体功能的特征。