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

• 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
• 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

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）显着降低了艾滋病毒相关的发病率和死亡率（1）。 然而，这不是一种实际的治疗方法，因为仅通过抗逆转录病毒疗法根除艾滋病毒估计需要60多年的时间。 治疗（1，2）。大量研究支持HIV特异性T细胞应答对于有效靶向至关重要 以及清除作为慢性感染源的HIV感染细胞（3 - 10）。不幸的是，病毒逃逸 并且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，人们对开发 靶向和消除HIV感染细胞以实现病毒免疫的新方法 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细胞免疫疗法已经显示出巨大的前景， 血癌（18 - 20），现在也证明了在恒河猴中减轻HIV/SIV感染的潜力 (21，22）和人源化小鼠（23 - 28）。我们最近发现，HIV特异性的基于CD4的双重CAR T细胞共表达， 表达独立的4 - 1BB和CD28共刺激结构域限制HIV复制并降低病毒负荷 在人源化小鼠中（23）。然而，目前使用自体T细胞来衍生CAR T细胞产物的局限性在于， （TCP），包括耗时和昂贵的制造，患者来源的T细胞不足或功能障碍， 和患者间TCP的异质性是其广泛应用于人类疾病的障碍。 然而，开发来自健康人类供体的同种异体TCP可以提供一种"现成的" 克服这些障碍的治疗选择，以及加速CAR T细胞疗法的使用（29 - 38）。 不幸的是，接受者免疫系统的输注后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， （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。 对抗艾滋病病毒。基于我们将有效的多重碱基编辑应用于CAR T细胞的初步数据，我们 假设碱基编辑方法和最佳同种异体供体鉴定都将使 开发一种具有增强疗效的抗同种异体排斥的基于CD4的CAR TCP，以消除HIV感染者。 为了验证这一假设，我们提出了以下具体目标： 目的1：确定对同种异体T细胞的遗传修饰是否可以增加其在体内的表达。 坚持不懈 目的2：鉴定与增强的免疫应答相关的同种异体HIV特异性CD4CAR T细胞的特征。 持久性和抗病毒功效。 目的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Aim 1和Aim 2的改善同种异体功能的特征。