Designer T Cell Therapy for PML

针对 PML 的设计师 T 细胞疗法

• 批准号: 6890927
• 负责人: RICHARD P. JUNGHANS
• 金额: $ 35.9万
• 依托单位: ROGER WILLIAMS HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-01 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6890927
• 关键词: HIV infections; Polyomavirus hominis 2; T cell receptor; T lymphocyte; biotechnology; cell communication molecule; cellular immunity; chimeric proteins; clinical trial phase I; fusion gene; gene therapy; human subject; human therapy evaluation; immunologic receptors; immunotherapy; molecular cloning; patient oriented research; progressive multifocal leukoencephalopathy; receptor expression

DESCRIPTION (provided by applicant): Progressive multifocal leukoencephalopathy (PML) is a deadly brain disease caused by the JC polyomavirus (JCV). PML arises in subjects with immunodeficiency in which specific T cells against JCV are lacking, as seen by the absence of T cell receptors (TCRs) recognizing JCV peptides. It is the goal of this proposal to provide to PML patients the missing anti-viral specificity through a new T cell immunotherapeutic strategy. To achieve this, we will perform ex vivo gene therapy on patients' own T cells to express TCR molecules that recognize JCV-infected cells. These TCRs are in turn genetically fused to molecular domains of T cell signaling molecule(s) to create chimeric immune receptors (CIRs) that regulate the T cell activity. We refer to TCR-based CIRs as "TCRCIR". In this application, we propose a staged development and application of anti-JCV designer T cells with our most advanced 2nd generation (Signal 1 + 2) constructs of CIRs, to take them through preclinical development to actual clinical trials. We propose an associated laboratory research program to monitor these studies, and to develop newer, 3rd generation designer T cells that are IL2 independent. Specific Aims for this four-year clinical development application are: Preclinical: To develop anti-JCV "designer T cells": (1) to clone JCV p36- and plOO-specific TCRs from HLA-A2 + PML survivors; (2) to create and test DNA constructs of JCV-specific TCRCIRs in 2nd generation in human T cells and (3)to create and test DNA constructs of JCV-specific TCRCIRs in 3rd generation form in human T cells; Clinical: (4) to perform Phase I clinical trial of 2nd generation anti-JCV designer T cells. By this plan, it is hoped that designer T cells will survive and expand in JCV + lesions in vivo, and eliminate JCV-infected cells. If functioning as intended, the application of anti-JCV designer T cells will parallel in vivo observations of CD8 + JCV-reactive T cells in PML-survivors and induce a "survivor" phenotype in patients who lack such cells endogenously.

描述（由申请人提供）：进行性多灶性脑白质病（PML）是由JC多瘤病毒（JCV）引起的致命脑部疾病。PML发生于免疫缺陷患者，缺乏针对JCV的特异性T细胞，如缺乏识别JCV肽的T细胞受体（TCRs）。该建议的目标是通过新的T细胞免疫治疗策略为PML患者提供缺失的抗病毒特异性。为了实现这一点，我们将对患者自身的T细胞进行体外基因治疗，以表达识别jcv感染细胞的TCR分子。这些tcr依次在遗传上融合到T细胞信号分子的分子域，以产生调节T细胞活性的嵌合免疫受体（CIRs）。我们将基于tcrr的cirr称为“TCRCIR”。在本申请中，我们建议分阶段开发和应用我们最先进的第二代（Signal 1 + 2） CIRs结构的抗jcv设计T细胞，使它们从临床前开发进入实际临床试验。我们提出了一个相关的实验室研究计划来监测这些研究，并开发新的，第三代设计的T细胞是IL2独立的。这项为期四年的临床开发申请的具体目标是：临床前：开发抗JCV“设计T细胞”：(1)从HLA-A2 + PML幸存者中克隆JCV p36和plo特异性tcr；(2)在人T细胞中创建和测试jcv特异性TCRCIRs的第二代DNA构建体；(3)在人T细胞中创建和测试jcv特异性TCRCIRs的第三代DNA构建体；临床：(4)开展第二代抗jcv设计T细胞I期临床试验。通过该方案，希望设计T细胞能够在体内在JCV +病变中存活和扩增，并消灭JCV感染的细胞。如果功能符合预期，抗jcv设计T细胞的应用将与pml幸存者体内CD8 + jcv反应性T细胞的观察平行，并在内源性缺乏此类细胞的患者中诱导“幸存者”表型。