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

基本信息

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
项目类别：
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

项目摘要

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，但未治愈。虽然药物可以防止感染传播，但它无法清除为病毒提供病毒的潜伏性病毒库 (LR) 或持久性病毒库 (PR)。据称，目前尚无可能实现艾滋病毒的绝育治疗，而“功能性治疗”应该作为一种更合适且可实现的目标而引起我们的关注。功能性治疗利用了 HIV 生命周期中的一个脆弱步骤：病毒需要 CD4 结合才能进入细胞，然而，逃避 MHC 呈递或抗体结合的 gp120 突变可能会阻碍免疫反应，但不会影响感染性，病毒 gp120 的任何突变都会阻碍感染性。 CD4 结合将破坏病毒的感染性，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。基于CD4的抗HIV CAR（CD4-TCR¿ ）之前已准备好重定向 CTL 以 MHC 非限制性方式杀死 HIV gp120+ 细胞，然而，自体 CD4 过继转移的临床试验。尽管输注一年后，设计者 T 细胞在配方中持续存在，但设计者 T 细胞未能控制病毒感染。失败的机制被认为包括：激活诱导细胞死亡 (AICD)、信号和细胞因子缺陷、调节性 T 细胞。该提案的初步数据中解决了许多这些假设，这些数据是在 NIH R21 资助下获得的。作为回应，我们创建了一种通过 T 细胞激活增强的 CAR。一种 2 信号格式，可提供共刺激信号（例如 CD28；信号 2）以创建第二代 (gen) 设计 T 细胞。我们的初步研究表明，该构建体对感染靶标具有高细胞毒性，并且在关键方面具有优越性。该模式的临床测试，包括潜在更新的感染细胞的暴露和靶向。本研究的目的包括 1. 预期临床应用的第二代药物的完整表征， 2. 使用针对 CCR5 的 siRNA 和病毒 Tat/Rev 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 的抗感染性和改进的有效性HIV 抑制；以及 4. 如果需要的话，继续研究和开发更先进的第四代药物，以供以后的临床开发使用。 dTc 在 HIV/AIDS 中的试验。首次使用 dTc 的目的是在 HAART 期间施用，以建立消除持久性病毒库和减少残留病毒血症的原理验证（如果 HAART 有效）。然后撤回，对持续抑制的观察相当于“功能性治愈”，当细胞重新激活时，将其从潜伏库中消除。体外模型表明，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“灭菌治疗”的前景，无论治愈是功能性的还是灭菌性的，这都将是最重要的进步。自 HAART 以来的 HIV 治疗。