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) 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 治疗 (1, 2)。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 消除作为慢性感染源的 HIV 感染细胞 (3-10)。不幸的是，病毒逃脱了 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，人们对开发的兴趣越来越大 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 细胞可以共同 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 在人源化小鼠中 (23)。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 对抗艾滋病毒。基于我们对 CAR T 细胞应用高效多重碱基编辑的初步数据，我们 假设碱基编辑方法和最佳同种异体供体的鉴定都将使 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 细胞并在没有 ART 的情况下抑制 HIV。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， 结合了 Aim 1 和 2 改进的同种异体功能的特征。