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：
10480991
负责人：
TODD M ALLEN
金额：
$ 48.86万
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/10480991
关键词：
Address Allogenic Anti-Retroviral Agents Autologous B-Cell Acute Lymphoblastic Leukemia Berlin 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 Life 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 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 mortality mouse model novel prevent prophylactic response stem cells success transcriptomics tumor vector-based vaccine vector-induced 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：抗逆转录病毒疗法（ART）大大降低了与HIV相关的发病率和死亡率（1）。但是，这不是实际的治疗治疗（1、2）。众多研究支持HIV特异性T细胞反应对于有效靶向至关重要消除是慢性感染来源的HIV感染细胞（3-10）。不幸的是，病毒逃生在这些功能的效力下，功能性病毒特异性效应子CD8+ T细胞的存在有限长期感染的个体的反应（11-17）。因此，人们对发展的兴趣越来越大新型免疫治疗方法靶向和消除感染HIV的细胞以实现病毒在没有艺术的情况下，抑制作用是“功能治愈”。嵌合抗原受体（CAR）T细胞免疫疗法表现出了很大的希望血液癌（18-20），现在也证明了减轻恒河猴中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的CAR T细胞共同表达独立的4-1BB和CD28共刺激域限制HIV复制并减少病毒伯嫩在人性化的小鼠中（23）。但是，使用自体T细胞得出CAR T细胞产物的当前局限性（TCP），包括耗时且昂贵的制造，不足或功能失调的患者T细胞， TCP的患者间异质性是其宽度应用于人类疾病的障碍。但是，从健康的人类捐助者中衍生出的同种异体TCP可以提供“现成” 克服这些障碍的治疗选择，并加速使用CAR T细胞疗法（29-38）。不幸的是，接收者免疫系统消除输注后仍然是一个重大障碍（39-41）。在这里，我们建议利用我们在Car T细胞生物学方面的专业知识（21、23、25、26、42、43），基础编辑（44-49）和HIV感染的人源化小鼠模型（50-58），以开发同种异体CAR T细胞疗法反对艾滋病毒。在我们的初步数据基础上，将有效的多重碱基编辑应用于CAR T细胞，我们假设基础编辑方法和对最佳替代捐赠者的识别都将使开发具有提高效率的基于耐药的CD4 CAR TCP，以消除HIV感染细胞并在没有艺术的情况下抑制HIV。为了检验这一假设，我们提出了以下特定目的：目标1：确定对同种异体T细胞的遗传修饰是否可以增强其体内持久性。 AIM 2：确定与增强的同种异HIV特异性CD4CAR T细胞的特征持久性和抗病毒效率。 AIM 3：比较同种异体与自体HIV特异性CD4CAR T细胞的体内HIV效率，将AIM 1和2的签名纳入改进的同种异体功能。