Designer T Cell Therapy for PML

描述(申请人提供)：进行性多灶性白质脑病(PML)是由JC多瘤病毒(JCV)引起的一种致命的脑部疾病。PML发生在免疫缺陷的受试者中，其中缺乏针对JCV的特异性T细胞，表现为缺乏识别JCV多肽的T细胞受体(TCR)。这项建议的目的是通过一种新的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细胞进行体外基因治疗，以表达识别JCV感染细胞的TCR分子。这些TCR又在基因上与T细胞信号分子(S)的分子结构域融合，产生调节T细胞活性的嵌合免疫受体(CIR)。我们将基于TCR的CIRS称为“TCRCIR”。在这项应用中，我们提出了分阶段开发和应用我们最先进的第二代(信号12)CIRS结构的抗JCV设计者T细胞，将它们从临床前开发带到实际的临床试验。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者T细胞，这些T细胞不依赖于IL2。这项为期四年的临床开发应用的具体目标是：临床前：开发抗JCV“设计型T细胞”：(1)从人类白细胞抗原A2 PML幸存者中克隆JCV p36和Ploo特异性TCRs；(2)在人类T细胞中创建并测试第二代JCV特异性TCRCIR的DNA结构；(3)在人类T细胞中创建并测试第三代JCV特异性TCRCIRs的DNA结构；(4)进行第二代抗JCV设计型T细胞的I期临床试验。通过这一计划，希望设计的T细胞能够在体内的JCV病变中存活和扩增，并消除JCV感染的细胞。如果发挥预期的作用，应用抗JCV设计者T细胞将在体内观察PML幸存者中CD8 JCV反应的T细胞，并在内源性缺乏此类细胞的患者中诱导出“幸存者”表型。

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.