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治疗相结合，具有根除病毒感染库的潜力的免疫疗法可能是抑制或治愈HIV/AIDS的有效手段。通过基因修饰表达嵌合免疫受体（CIRs）的T细胞可以重定向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CIRs。到目前为止，最有希望的抗hiv CIR是CD4zeta (CD4?)，它通过CD4细胞外结构域以MHC非限制性方式特异性针对HIV-1 gp120抗原。然而，自体CD4？在临床试验中，HIV/AIDS患者的t细胞未能控制病毒感染，尽管有一定比例的过继性CD4？受体t细胞输注后可存活1年。失败的机制尚不清楚。迄今为止，所有抗hiv CIRs都是简单的tcr信号（信号1）分子。我们和其他实验室的结果表明，CIRs可以通过提供共刺激信号（例如CD28；信号2）来增强其在T细胞活化中的效力。我们的初步结果表明，基于CD4的抗hiv CIRs仅具有TCR信号1或信号1+2(即第一代CD4？第二代CD4CD28？包括信号2在内的CIRs在逆转录病毒转导的人类T细胞上同样表现良好。该建议的基本原理是：(1)通过包含CD28信号来增强基于cd4的抗hiv CIR的CD8+设计T细胞的效力，以及(2)优化带有1+2信号（CD4CD28?）的基于cd4的CIR的设计。我们将构建和比较一组不同设计的基于cd4的CIRs，包括三个CD4CD28？不同的设计，因为它们对抗原刺激的激活能力，对诱导能量的易感性和对HIV感染的易感性。我们还将在异种移植小鼠模型中评估它们针对HIV抗原（gp120）表达细胞的体内免疫治疗效果。如果证明比第一代带有抗hiv CIR CD4的抗hiv设计T细胞更有效？新设计的第二代T细胞具有最佳的CD4CD28？设计将成为一类新的免疫治疗试剂，以提高特异性T细胞过继转移治疗HIV/AIDS的临床效果。

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.