A Phase I Study of Lentivirus Safety During T-Cell Immu

T 细胞免疫过程中慢病毒安全性的 I 期研究

• 批准号: 6850626
• 负责人: John A Zaia
• 金额: $ 41.22万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-01 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6850626
• 关键词: AIDS therapy; Lentivirus; RNA interference; T cell receptor; T lymphocyte; antiAIDS agent; blood chemistry; cell differentiation; clinical trial phase I; cytotoxicity; gene therapy; host organism interaction; human subject; human therapy evaluation; immunotherapy; patient oriented research; small interfering RNA; statistics /biometry; therapy design /development; transfection /expression vector

The clinical trial component of this proposal consists of a phase I study of lentiviral vector transduced T-cells expressing anti-HIV siRNA (J. Zaia, P.I.). This will be the first trial of anti-HIV siRNA in humans and will be performed at City of Hope with collaboration from C. June at UPENN and M. Jensen at COH. The goals of the study are to determine the feasibility and safety of lentiviral transduction and expansion of T-cells from AIDS patients who have failed HAART. The preclinical and the clinical aspects of T-cell function will be characterized by C. June after transduction and expression of anti-HIV RNAs. He will provide important GMP manufacturing scale up support for the clinical trial in Project 5 in the areas of expansion technology and analysis of the function of T-cell after transduction and selection. In anticipation of a T cell selection system, the effect of IMPDH on T cell function and the safety of lentivirus integration will be explored. The specific aims are as follows: Aim 1: To determine the feasibility and safety of RNAi-lentivirus transduced T cell immunotherapy in the setting of AIDS: Study 1: The lentivirus vector, pHIV7-shII, has been selected for clinical phase I studies based on comparative anti-HIV effect in vitro (see PRELIMINARY RESULTS). This vector was developed in our current IPCP activity by J. Rossi and J.K. Yee, and it is a self-inactivating lentivirus vector encoding a short hair-pin RNAi targeting an exon in HIV-1 rev. The clinical grade T cell product will be characterized for immune function, TCR repertoire, and resistance to HIV before and after infusion into research patients. In this study, the T cell collection, transduction, and expansion will be performed at BRICOH in Core C, and the subjects will be treated in the GCRC. The biologic effect of this transduction on cells pre- and post-infusion will be evaluated. Study 2: To determine the safety and relative efficacy of a lentivirus encoding a multiplex RNAi developed in this IPCP. Using the first generation pHIV7-shlI lentivirus vector evaluated in aim 1 for comparison, a second clinical trial will evaluate the relative survival of T cells transduced with a multi-plexed RNAi vector developed in Projects 1-3. In this second clinical trial, subjects will receive combined T cells transduced with either the fast generation RNAi vector or with the improved vector and then observed for relative T cell survival in the presence of HIV. Aim 2: To characterize the function of T cells after in vitro expansion and selection: The immunologic function of T cells expanded after lentivirus RNAi transduction and after transduction with new vectors developed in Projects 1-3 will be studied. A particular focus of this work will be the effect of T cell selection and expansion, using either IMPDH2- or MGMT-based methods, on the immunologic function of these cells in vitro and on the anti-HIV effect. This will contribute to the safety phase of study #1 and to the pre-clinical phase of study #2.

该提案的临床试验组成部分包括对表达抗HIV siRNA的慢病毒载体转导的T细胞的I期研究（J. Zaia，P.I。）。这将是人类反HIV siRNA的首次审判，将在霍普市与C. June的合作和COH的M. Jensen合作在Hope进行。该研究的目标是确定慢病毒转导的可行性和安全性，并从HAART失败的艾滋病患者中扩展T细胞。 T细胞功能的临床前和临床方面的特征是C.在抗HIV RNA的转导和表达后6月。他将在项目5的扩展技术领域和转导和选择后对项目5的临床试验提供重要的GMP制造规模。为了预期T细胞选择系统，将探讨IMPDH对T细胞功能和慢病毒整合安全性的影响。具体目的如下： AIM 1：确定RNAi-Lentivirus在AIDS的情况下转导T细胞免疫疗法的可行性和安全性： 研究1：慢病毒载体PHIV7-SHII已根据体外比较抗HIV效应选择临床I期研究（请参阅初步结果）。该向量是由J. Rossi和J.K.在我们当前的IPCP活动中开发的。 Yee，这是一个自动灭活的慢病毒载体，编码了针对HIV-1 Rev中外显子的短发针RNAi。临床级T细胞产物的特征是免疫功能，TCR曲目和对研究患者输注之前和之后对HIV的耐药性。在这项研究中，T细胞收集，转导和扩张将在Core C的BricoH上进行，并且将在GCRC中对受试者进行治疗。将评估这种转导对输注前后细胞的生物学作用。 研究2：确定编码本IPCP中开发的多重RNAi的慢病毒的安全性和相对功效。使用在AIM 1中评估的第一代PHIV7-SHLI慢病毒载体进行比较，第二次临床试验将评估在项目1-3中开发的多质子RNAi载体转导的T细胞的相对存活。在第二次临床试验中，受试者将接收与快速产生的RNAi载体转导的T细胞或改进的载体，然后在HIV存在下观察到相对T细胞的存活。 目标2：在体外扩张和选择后表征T细胞的功能： T细胞的免疫功能将在RNAi转导后扩展，并在项目1-3中开发的新向量转导后扩展。这项工作的一个特殊重点将是使用基于IMPDH2-或MGMT方法的T细胞选择和扩展的影响，对这些细胞在体外和抗HIV效应中的免疫功能。这将有助于研究＃1的安全阶段和研究＃2的临床前阶段。