Potent Designer T cells for HIV/AIDS Immunotherapy

用于 HIV/艾滋病免疫治疗的有效设计 T 细胞

• 批准号: 7459905
• 负责人: RICHARD P. JUNGHANS
• 金额: $ 20.97万
• 依托单位: ROGER WILLIAMS HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-15 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7459905
• 关键词: AIDS/HIV problem; Adoptive Transfer; Antigens; Antiviral Agents; Autologous; CD28 gene; CD3 Antigens; CD4 Antigens; CD4 Positive T Lymphocytes; CD8B1 gene; Cell Death; Cells; Class; Clinical; Clinical Trials; Extracellular Domain; Failure; Generations; Genes; HIV Antigens; HIV Envelope Protein gp120; HIV Infections; HIV-1; Human; Immunologic Receptors; Immunotherapeutic agent; Immunotherapy; In Vitro; Infusion procedures; Laboratories; Link; Modification; Outcome; Patients; Pharmacotherapy; Phase; Predisposition; Reagent; Resistance; Retroviral Vector; Safety; Signal Transduction; T-Cell Activation; T-Lymphocyte; Testing; Upper arm; Viral; Virus; Virus Diseases; Xenograft procedure; anergy; base; design; improved; in vivo; killings; mouse model; receptor expression; retroviral transduction; tumor

DESCRIPTION (provided by applicant): Immunotherapies that have the potential to eradicate reservoirs of viral infection may be a useful means to suppress or cure HIV/AIDS in combination with current antiviral drug therapies that only inhibit viral replication. T cells expressing chimeric immune receptors (CIRs) through gene modification can be redirected to kill tumor or virus-infected cells. Several forms of CIRs specific to HIV antigens have been developed. So far, the most promising anti-HIV CIR and the only one that has been tested in clinical trials is CD4zeta (CD4?), which is specific to HIV-1 gp120 antigen in MHC nonrestricted fashion through its CD4 extracellular domain. However, the adoptive transfer of autologous CD4?-T cells to HIV/AIDS patients failed to control the viral infection in clinical trials, despite the persistence of a percentage of adoptively transferred CD4?-T cells in recipients for up to 1 year after infusion. The mechanisms of failure are unknown. To date, all anti-HIV CIRs have been simple TCR-signal (Signal 1) molecules. Results from our laboratory and others have demonstrated that CIRs can be enhanced in their potency in T cell activation by providing co-stimulatory signal (e.g., CD28; Signal 2). Our preliminary results indicated that CD4-based anti-HIV CIRs with TCR Signal 1 alone or Signal 1+2 (i.e., 1st generation CD4? and 2nd generation CD4CD28? CIRs that include Signal 2) expressed equally well on retrovirally transduced human T cells. The rationales of this proposal are (1) to enhance the potency of anti-HIV CD8+ designer T cells with the CD4-based anti-HIV CIR by including CD28 signaling, and (2) to optimize the design of CD4-based CIRs with Signals 1+2 (CD4CD28?). We will construct and compare a panel of CD4-based CIRs of different designs with or without CD28 signaling, including three CD4CD28? of different designs, for their potencies in activation upon antigen stimulation, susceptibility to induction of anergy and susceptibility to HIV infection. We will also evaluate their in vivo immunotherapeutic efficacy in targeting HIV antigen (gp120)-expressing cells in a xenografted mouse model. If proven more potent than the 1st generation anti-HIV designer T cells armed with anti-HIV CIR CD4?, the new 2nd generation of designer T cells with optimal CD4CD28? design will serve as a new class of immunotherapy reagents to enhance the clinical outcome of adoptive transfer of specific T cells for HIV/AIDS.

描述（由申请人提供）：有可能根除病毒感染库的免疫疗法与目前仅抑制病毒复制的抗病毒药物疗法相结合，可能是抑制或治愈艾滋病毒/艾滋病的有用手段。通过基因修饰表达嵌合免疫受体 (CIR) 的 T 细胞可以被重定向来杀死肿瘤或病毒感染的细胞。已经开发出几种针对 HIV 抗原的 CIR 形式。迄今为止，最有前途的抗 HIV CIR 也是唯一在临床试验中经过测试的 CIR 是 CD4zeta (CD4?)，它通过其 CD4 胞外结构域以 MHC 非限制性方式特异性针对 HIV-1 gp120 抗原。然而，在临床试验中，将自体 CD4?-T 细胞过继转移给 HIV/AIDS 患者未能控制病毒感染，尽管输注后受者体内过继转移的 CD4?-T 细胞的百分比持续长达一年之久。 。失败的机制尚不清楚。迄今为止，所有抗 HIV CIR 都是简单的 TCR 信号（信号 1）分子。我们实验室和其他实验室的结果表明，CIR 可以通过提供共刺激信号（例如 CD28；信号 2）来增强 T 细胞激活的效力。我们的初步结果表明，基于 CD4 的抗 HIV CIR 与单独的 TCR 信号 1 或信号 1+2（即第一代 CD4? 和包括信号 2 的第二代 CD4CD28? CIR）在逆转录病毒转导的人类 T 细胞上表达同样良好。该提案的基本原理是（1）通过包含 CD28 信号传导来增强具有基于 CD4 的抗 HIV CIR 的抗 HIV CD8+ 设计 T 细胞的效力，以及（2）优化具有信号的基于 CD4 的 CIR 的设计1+2（CD4CD28？）。我们将构建并比较一组具有或不具有 CD28 信号传导的不同设计的基于 CD4 的 CIR，包括三个 CD4CD28？不同的设计，因为它们在抗原刺激下的激活效力、对诱导无反应的敏感性和对 HIV 感染的敏感性。我们还将评估它们在异种移植小鼠模型中针对表达 HIV 抗原 (gp120) 的细胞的体内免疫治疗功效。如果被证明比配备抗 HIV CIR CD4 的第一代抗 HIV 设计 T 细胞更有效，那么具有最佳 CD4 CD28 的新第二代设计 T 细胞将更有效。该设计将作为一类新型免疫治疗试剂，以增强针对 HIV/AIDS 的特异性 T 细胞过继转移的临床效果。