Genetic Approaches to Enhance the Anti-Tumor Functions of T Lymphocytes

增强 T 淋巴细胞抗肿瘤功能的遗传学方法

• 批准号: 7136186
• 负责人: MICHEL SADELAIN
• 金额: $ 17.76万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7136186
• 关键词: T lymphocyte; antigen receptors; genes; genetics; human; neoplasm /cancer; tumor antigens

The genetic modification of T lymphocytes is the basis for novel approaches to study and establish tumor immunity. The genetic transfer of antigen receptors is indeed a powerful approach to rapidly generate tumorspecific T lymphocytes. However, while necessary, tumor antigen recognition is not sufficient to permit tumor eradication. To achieve this goal, primed CTLs must expand to sufficient numbers, migrate to tumor sites, mature into effector cells and carry out their cytolytic function unimpeded. The genetic strategies we are pursuing aim to increase recognition of tumor antigens, enhance anti-tumor functions and sustain T cell function in cancer patients. Most important for our understanding of human tumor immunology and therapeutic goals, gene addition and knockdown strategies can be applied to human T lymphocytes, on which we focus in this project. The specific aims are based on our published and preliminary data. Aim 1: To investigate the biological properties and therapeutic potential of tumor specific CD8+ T cells co-stimulated by CD28 and 4-1BB. We hypothesize that concerted CD28 and 4-1BB signals sustain CD8+ T cell proliferation and survival, and may thus augment the therapeutic potency of genetically targeted T lymphocytes. Aim 2: To investigate the effect of ex vivo IL-15 on the proliferation, survival, differentiation and therapeutic potential of adoptively transferred human primary T lymphocytes. This aim builds on our recent finding that IL-15 enhances the therapeutic potential of cultured 19z1-transduced PBLs upon adoptive transfer to tumorbearing mice. We hypothesize that IL15 increases therapeutic efficacy through several mechanisms, most importantly T cell survival. Aim 3: To establish an efficient protocol for T'cell transduction and expansion in a closed system and perform a phase I clinical trial to assess the safety, persistence and therapeutic activity of autologous 19-28z-transduced T lymphocytes in patients with relapsed, chemo-refractory chronic lymphocytic leukemia. We hypothesize that patient T cells expressing a CD28/ -like chimeric antigen receptor will induce durable remissions, more so in cyclophosphamide-treated recipients. Our investigation critically depends on the Gene Transfer and Somatic Cell Engineering Core, to genetically modify patient T cells, the Imaging Core, to study T cell migration and persistence in vivo, and the Administrative Core, for biostatistics and data management.

T 淋巴细胞的基因修饰是研究和建立肿瘤新方法的基础 免疫。抗原受体的遗传转移确实是快速产生肿瘤特异性的有效方法 T淋巴细胞。然而，虽然有必要，但肿瘤抗原识别不足以允许肿瘤 根除。为了实现这一目标，引发的 CTL 必须扩增到足够的数量，迁移到肿瘤部位， 成熟为效应细胞并不受阻碍地执行其溶细胞功能。我们的遗传策略 追求的目标是增加对肿瘤抗原的识别，增强抗肿瘤功能并维持T细胞 在癌症患者中发挥作用。对于我们了解人类肿瘤免疫学和 治疗目标、基因添加和敲除策略可应用于人类 T 淋巴细胞， 我们在这个项目中关注的重点。具体目标基于我们已发布的初步数据。目标 1： 研究共刺激的肿瘤特异性 CD8+ T 细胞的生物学特性和治疗潜力 CD28 和 4-1BB。我们假设 CD28 和 4-1BB 信号协同维持 CD8+ T 细胞增殖 和存活率，从而可能增强基因靶向 T 淋巴细胞的治疗效力。目标 2： 研究离体 IL-15 对增殖、存活、分化和治疗潜力的影响 过继转移的人原代T淋巴细胞。这一目标建立在我们最近发现 IL-15 增强培养的 19z1 转导 PBL 在过继转移至荷瘤后的治疗潜力 老鼠。我们假设 IL15 通过多种机制提高治疗效果，大多数是 重要的是T细胞的存活。目标 3：建立 T 细胞转导和扩增的有效方案 封闭系统并进行 I 期临床试验，以评估其安全性、持久性和治疗活性 复发性化疗难治性慢性病患者的自体 19-28z 转导 T 淋巴细胞 淋巴细胞白血病。我们假设患者 T 细胞表达 CD28/ 样嵌合抗原 受体将诱导持久缓解，在环磷酰胺治疗的接受者中更是如此。我们的调查 关键取决于基因转移和体细胞工程核心，对患者 T 进行基因改造 细胞、成像核心，用于研究 T 细胞在体内的迁移和持久性，以及管理核心，用于研究 生物统计学和数据管理。