Potent Designer T cells for HIV/AIDS Immunotherapy

描述（由申请人提供）：与目前仅抑制病毒复制的抗病毒药物疗法联合使用，具有根除病毒感染储库潜力的免疫疗法可能是抑制或治愈HIV/AIDS的有用手段。通过基因修饰表达嵌合免疫受体（CIR）的T细胞可以被重定向以杀死肿瘤或病毒感染的细胞。已经开发了对HIV抗原特异性的几种形式的CIR。到目前为止，最有希望的抗HIV CIR和唯一一个已经在临床试验中测试的是CD 4 zeta（CD 4？），其通过其CD 4胞外结构域以MHC非限制性方式特异于HIV-1gp 120抗原。然而，自体CD 4？T细胞的艾滋病毒/艾滋病患者未能控制病毒感染的临床试验，尽管持续的百分比过继转移的CD 4？接受者的T细胞在输注后长达1年。失败的机制是未知的。迄今为止，所有抗HIV CIR都是简单的TCR信号（信号1）分子。来自我们实验室和其他实验室的结果已经证明，通过提供共刺激信号（例如，CD 28;信号2）。我们的初步结果表明，具有单独的TCR信号1或信号1+2（即，第一代CD 4？第二代CD 4CD 28？包括信号2的CIR）在逆转录病毒转导的人T细胞上同样良好地表达。该提案的基本原理是（1）通过纳入CD 28信号，增强抗HIV CD 8+设计T细胞与基于CD 4的抗HIV CIR的效力，以及（2）优化基于CD 4的CIR与信号1+2（CD 4CD 28？）的设计。我们将构建和比较一个面板的CD 4为基础的CIR的不同设计或没有CD 28信号，包括三个CD 4CD 28？不同的设计，因为它们在抗原刺激时激活的效力、对诱导无反应性的易感性和对HIV感染的易感性。我们还将评估它们在异种移植小鼠模型中靶向HIV抗原（gp 120）表达细胞的体内免疫效力。如果证明比配备抗HIV CIR CD 4？的第一代抗HIV设计者T细胞更有效，新的第二代设计师T细胞与最佳的CD 4CD 28？设计将作为一类新的免疫治疗试剂，以提高过继转移HIV/AIDS特异性T细胞的临床结果。

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.