Towards a new clinical trial Advanced infection proof anti HIV gene modified T ce

走向新的临床试验先进的感染证明抗HIV基因修饰T ce

• 批准号: 8683491
• 负责人: RICHARD P. JUNGHANS
• 金额: $ 17万
• 依托单位: ROGER WILLIAMS HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-15 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8683491
• 关键词: AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Address; Adoptive Transfer; Advocate; Affect; Anti-Retroviral Agents; Antibiotics; Antibodies; Antigen Receptors; Antigens; Apoptosis; Autologous; Award; Binding; CCR5 gene; CD28 gene; CXCR4 gene; Cell Communication; Cell Death; Cell Survival; Cells; Clinical; Clinical Trials; Consultations; Cytokine Signaling; Data; Development; Effectiveness; Effector Cell; Engineering; Excision; Extracellular Domain; Failure; Funding; Gene-Modified; Generations; Genes; Goals; HIV; HIV Envelope Protein gp120; HIV Infections; Highly Active Antiretroviral Therapy; Human; Hybrids; IL2 gene; Immune; Immunologic Surveillance; Infection; Infection prevention; Infusion procedures; Intention; Intervention; Life Cycle Stages; Memory; Modality; Modification; Mutate; Mutation; Patients; Pharmaceutical Preparations; Preclinical Testing; Predisposition; Principal Investigator; Production; Proteins; Reaction; Regulatory T-Lymphocyte; Relapse; Research; Residual state; Resistance; Resistance to infection; Rest; Signal Transduction; Small Interfering RNA; Solutions; T-Cell Activation; T-Lymphocyte; Therapeutic; Therapeutic Effect; Toxic effect; United States National Institutes of Health; Vaccines; Viral; Viral Proteins; Viremia; Virus; Virus Diseases; Withdrawal; anergy; base; clinical application; cytokine; cytotoxic; design; immune clearance; improved; in vitro Model; in vivo; killings; latent infection; mouse model; novel; pre-clinical; prevent; purge; research and development; research clinical testing; response; zeta chain antigen T cell receptor

DESCRIPTION (provided by applicant): HIV is driven to low levels on HAART therapy but is not cured. While infectious spread is prevented by drugs, it does nothing to purge the latent reservoir (LR) or persistent reservoir (PR) that provide viruses for relapse of infection when HAART is removed. It has been said that there is no present likelihood for a sterilizing cure for HIV, and that a "functional cure" should attract our focus as a more suitable and attainable goal. An alternative approach with potential for functional cure exploits a vulnerable step in the life cycle of HIV: the virus requires CD4 binding to enter the cell. Whereas mutations of gp120 that escape MHC presentation or antibody binding may thwart the immune reaction without affecting infectivity, any mutation of viral gp120 that blocks CD4 binding will destroy virus infectivity. T cells expressing chimeric antigen receptors (CARs) through gene modification ("designer T cells", dTc) can be redirected to kill virus-infected cells. A CD4 based anti-HIV CAR (CD4-TCR¿) was previously prepared that redirects CTL to kill HIV gp120+ cells in an MHC non-restricted fashion. However, clinical trials of adoptive transfer of autologous CD4¿ designer T cells failed to control viral infection, despite a persistent fraction of designer T cells in recipents one year after infusion. The mechanisms of failure were proposed to include: activation induced cell death (AICD), deficiencies of signals and cytokines, regulatory T cell suppression, and heightened susceptibility of designer T cells to HIV infection. Many of these suppositions were addressed in the preliminary data for this proposal that were obtained under prior NIH R21 funding. In response, we created a CAR enhanced for potency in T cell activation via a 2-signal format that provides co-stimulatory signal (e.g., CD28; Signal 2) to create 2nd generation (gen) designer T cells. Our preliminary studies indicate high cytotoxic potency against infected targets and superiority of this construct in key aspects to justify a renewed clinical test of this modalit, including potentially the exposure and targeting of latently infected cells. Aims for this study include 1. Complete characterization of a 2nd gen agent in anticipation of a clinical application, 2. "Infection-proof" the dTc with siRNA against CCR5 and viral Tat/Rev to create a 3rd gen dTc; 3. Conduct in vivo correlate studies in a humanized mouse model to demonstrate resistance to infection of the new dTc and improved effectiveness in HIV suppression; and 4. Continuing research and development for still more advanced, 4th generation, agents for later clinical development, if needed. Anticipated results from these new products would justify new clinical trials for dTc in HIV/AIDS. The intention of the dTc first use will be to administer during HAART to establish a proof-of-principle in terms of eliminating the Persistent Reservoir and reducing residual viremia. This compartment is always gp120+. If HAART is then withdrawn, observation of a continued suppression would be tantamount to a "functional cure", eliminating cells from the Latent Reservoir as they reactivate. We have shown with an in vitro model that dTc-secreted cytokine can also induce latent cells to re-express viral proteins, rendering them vulnerable to elimination, raising the prospect of a "sterilizing cure". Whether a cure is functional or sterilizng, it would be the most significant advance in HIV treatment since HAART.

描述(申请人提供)：HIV在HAART治疗中被驱动到低水平，但没有治愈。虽然药物可以防止传染病的传播，但当HAART被移除时，它对清除潜伏性蓄水池(LR)或持久性蓄水池(PR)没有任何作用，这些潜伏性蓄水池或持久性蓄水池为感染复发提供病毒。有人说，目前没有对艾滋病毒进行绝育治疗的可能性，而“功能性治疗”应该作为更合适和更可实现的目标来吸引我们的注意力。另一种有可能实现功能性治愈的方法利用了艾滋病毒生命周期中的一个脆弱步骤：病毒需要与CD4结合才能进入细胞。尽管逃脱MHC呈递或抗体结合的gp120突变可能会在不影响传染性的情况下阻碍免疫反应，但任何阻止CD4结合的病毒gp120突变都会破坏病毒的传染性。通过基因修饰表达嵌合抗原受体(CARS)的T细胞(“设计型T细胞”，DTC)可以被重定向以杀死感染病毒的细胞。之前已经准备了一种基于CD4的抗HIV CAR(CD4-TCR？)，它可以重定向CTL，以MHC非限制性方式杀死HIV gp120+细胞。然而，尽管输注一年后食谱中持续存在一部分设计T细胞，但过继转移自体设计T细胞的临床试验未能控制病毒感染。失败的机制被认为包括：激活诱导的细胞死亡(AICD)，信号和细胞因子的缺乏，调节性T细胞抑制，以及设计型T细胞对HIV感染的易感性增加。许多这些假设在这项提案的初步数据中得到了解决，这些数据是在之前的NIH R21资助下获得的。作为回应，我们创造了一种CAR，通过提供共刺激信号(例如，CD28；信号2)的双信号格式来增强T细胞激活的效力，以创建第二代(Gen)设计T细胞。我们的初步研究表明，对感染靶标具有很高的细胞毒力，而且该结构在关键方面具有优越性，因此有理由对该模型进行新的临床测试，包括潜在地暴露和靶向潜伏感染的细胞。这项研究的目的包括1。第二代制剂的完整特征，期待临床应用，2。3.在人源化小鼠模型中进行体内相关性研究，以证明新的DTC对感染的抵抗力和提高抑制艾滋病毒的有效性；以及4.如果需要，继续研发更先进的第4代药物，用于以后的临床开发。这些新产品的预期结果将证明DTC治疗艾滋病毒/艾滋病的新临床试验是合理的。DTC首次使用的目的将是在HAART期间实施，以建立消除持久性储存库和减少残余病毒血症的原则证明。这个隔间的温度始终为gp120+。如果HAART随后被撤销，观察到持续的抑制将等同于“功能治愈”，当细胞重新激活时，消除潜伏库中的细胞。我们已经用体外模型表明，DTC分泌的细胞因子也可以诱导潜伏细胞重新表达病毒蛋白，使它们容易被消除，从而增加了“消毒疗法”的可能性。无论治愈是有效的还是绝育的，这都将是自HAART以来艾滋病毒治疗方面最重大的进步。