Designer T Cell Therapy for PML

针对 PML 的设计师 T 细胞疗法

• 批准号: 7057815
• 负责人: RICHARD P. JUNGHANS
• 金额: $ 35.06万
• 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 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7057815
• 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）：进行性多灶性白质脑病（PML）是一种由 JC 多瘤病毒（JCV）引起的致命性脑部疾病。 PML 发生在患有免疫缺陷的受试者中，其中缺乏针对 JCV 的特异性 T 细胞，如缺乏识别 JCV 肽的 T 细胞受体 (TCR) 所示。该提案的目标是通过新的 T 细胞免疫治疗策略为 PML 患者提供缺失的抗病毒特异性。为了实现这一目标，我们将对患者自身的 T 细胞进行离体基因治疗，以表达识别 JCV 感染细胞的 TCR 分子。这些 TCR 依次与 T 细胞信号分子的分子域进行基因融合，形成调节 T 细胞活性的嵌合免疫受体 (CIR)。我们将基于 TCR 的 CIR 称为“TCRCIR”。在此应用中，我们建议使用我们最先进的第二代（信号 1 + 2）CIR 构建体来分阶段开发和应用抗 JCV 设计 T 细胞，以将其从临床前开发过渡到实际临床试验。我们提出了一个相关的实验室研究计划来监测这些研究，并开发独立于 IL2 的更新的第三代设计 T 细胞。这个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幸存者克隆JCV p36-和p100-特异性TCR； (2) 在人 T 细胞中创建并测试第二代 JCV 特异性 TCRCIR 的 DNA 构建体，以及 (3) 在人 T 细胞中创建并测试第三代形式的 JCV 特异性 TCRCIR 的 DNA 构建体；临床：（4）进行第二代抗JCV设计T细胞的I期临床试验。通过这一计划，希望设计的T细胞能够在体内JCV+病灶中存活和扩增，并消除JCV感染的细胞。如果按预期发挥作用，抗 JCV 设计 T 细胞的应用将与 PML 幸存者中 CD8 + JCV 反应性 T 细胞的体内观察平行，并在内源性缺乏此类细胞的患者中诱导“幸存者”表型。