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（由申请人提供）：HAART 治疗使 HIV 水平降至较低水平，但并未治愈。虽然药物可以防止感染传播，但它对于清除潜伏病毒库（LR）或持久病毒库（PR）没有任何作用，这些病毒在HAART去除后为感染复发提供病毒。有人说，目前不可能对艾滋病毒进行绝育治疗，而“功能性治疗”应该作为一个更合适和可实现的目标而引起我们的关注。另一种具有功能性治愈潜力的方法利用了 HIV 生命周期中的一个脆弱步骤：病毒需要结合 CD4 才能进入细胞。虽然逃避 MHC 呈递或抗体结合的 gp120 突变可能会阻碍免疫反应而不影响感染性，但病毒 gp120 的任何阻止 CD4 结合的突变都会破坏病毒的感染性。通过基因修饰表达嵌合抗原受体 (CAR) 的 T 细胞（“设计 T 细胞”，dTc）可以被重定向以杀死病毒感染的细胞。先前制备了基于 CD4 的抗 HIV CAR (CD4-TCR¿)，可重定向 CTL 以 MHC 非限制性方式杀死 HIV gp120+ 细胞。然而，自体 CD4 设计 T 细胞过继转移的临床试验未能控制病毒感染，尽管输注一年后，受试者体内仍残留有少量设计 T 细胞。 失败的机制被认为包括：激活诱导细胞死亡（AICD）、信号和细胞因子的缺陷、调节性 T 细胞抑制以及设计 T 细胞对 HIV 感染的敏感性增加。其中许多假设在该提案的初步数据中得到了解决，这些数据是在先前的 NIH R21 资助下获得的。作为回应，我们通过提供共刺激信号（例如 CD28；信号 2）的 2 信号格式创建了一种增强 T 细胞激活效力的 CAR，以创建第二代 (gen) 设计 T 细胞。我们的初步研究表明，该结构对感染靶标具有高细胞毒性，并且在关键方面具有优越性，证明了对该模式进行新的临床测试的合理性，包括潜在感染细胞的暴露和靶向。本研究的目标包括 1. 预期临床应用的第二代药物的完整表征，2. 使用针对 CCR5 和病毒 Tat/Rev 的 siRNA 对 dTc 进行“防感染”，以创建第三代 dTc； 3. 在人源化小鼠模型中进行体内相关研究，以证明新dTc对感染的抵抗力和艾滋病毒抑制效果的提高； 4. 如果需要，继续研究和开发更先进的第四代药物，用于以后的临床开发。这些新产品的预期结果将证明 dTc 在艾滋病毒/艾滋病方面进行新的临床试验是合理的。 dTc 首次使用的目的是在 HAART 期间施用，以在消除持久性病毒库和减少残留病毒血症方面建立原理验证。 这个隔间始终是gp120+。如果随后撤回HAART，观察到持续的抑制就相当于“功能性治愈”，当细胞重新激活时将其从潜伏库中消除。我们通过体外模型证明，dTc 分泌的细胞因子还可以诱导潜伏细胞重新表达病毒蛋白，使它们容易被消除，从而提高了“绝育疗法”的前景。无论是功能性治愈还是绝育性治愈，这都将是自 HAART 以来 HIV 治疗领域最重大的进步。