IMMUNOTHERAPY OF BREAST CANCER WITH TUMOR ANTIGEN SPECIFIC CYTOTOXIC T CELLS

使用肿瘤抗原特异性细胞毒性 T 细胞对乳腺癌进行免疫治疗

• 批准号: 6664501
• 负责人: HERBERT KIM LYERLY
• 金额: $ 17.92万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-01 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6664501
• 关键词: active immunization; breast neoplasms; cellular immunity; clinical research; clinical trial phase I; cytotoxic T lymphocyte; drug screening /evaluation; helper T lymphocyte; human subject; human therapy evaluation; human tissue; metastasis; neoplasm /cancer immunology; neoplasm /cancer immunotherapy; neoplasm /cancer vaccine; tumor antigens; tumor infiltrating lymphocyte; vector vaccine

The studies contained in Project 5 are based on the hypothesis that breast cancer patients mount detectable, albeit ineffective, cellular immune responses against well-conserved TAA expressed by their actively-growing tumors and that specific augmentation of these activities may provide improved host control of tumor outgrowth. The overall objective of Project 5 is, therefore, to characterize potential anti-TAA reactivities present in TIL and PBMC populations from breast cancer patients with tumors having well-defined TAA expression, and to use these pre-clinical findings as a framework for constructing rational Phase I immune-based therapeutic approaches. The scientific endeavors of the previous years have, in close collaboration with Core 4, focused on the establishment of a bank of paired tumor/Til/PBMC specimens from women who have had surgical intervention for treatment of their breast cancer. This specimen bank currently contains clinical material from over 80 patients. Using combined molecular and immunohistochemical techniques, disaggregated tumor specimens are assessed for specific TAA expression and, based on the mosaic of TAA expressed by an individual tumor, TIL and PBMC are analyzed for the presence of immune reactivities against those specific antigens. Assays aimed at detecting both helper T cell and precursor CTL (CTL/p) activities form the basis for these immunologic analyses. Major efforts in Years 4&5 will be focused on completion of the analyses. In addition, a Phase I clinical trial involving direct administration of a recombinant canary pox-MAGE-1/3 minigene vector to HLA-A1 patients with MAGE-1 and/or MAGE-3 expressing tumors will begin in mid-Year 3 and, most likely, carry through Year 4 and part of Year 5. Although the principal goals of this trial are safety and toxicity, major laboratory emphasis will be placed on monitoring enrolled patients for development and enhancement of responses to the specific minigenes. Assays aimed at measuring and quantitating helper T cell and CTL precursors activities will serve as the mainstay of the immunologic assessments. Collectively, these approaches are designed to expand our current working knowledge of host responses against autologous breast tumors and to utilize these findings in formulating rational, antigen-specific, immune-based therapies. The studies in Years 4&5 will allow us to test these concepts in the context of a Phase I clinical trial and to further build a foundation for future trials.

项目5中包含的研究基于这样的假设：乳房 癌症患者建立可检测的细胞免疫，尽管无效 其活跃生长表达对保存完好的TAA的反应 肿瘤以及这些活动特定增强可提供 改善了对肿瘤生长的宿主控制。项目的总体目标 因此，5是为了表征存在的潜在的抗TAA反应性 乳腺癌患者外周血中的TIL和PBMC 明确的TAA表达，并将这些临床前发现作为 构建合理的I期免疫治疗框架 接近了。前几年的科学努力已经接近尾声 与核心4合作，重点是建立一家 手术后妇女的肿瘤/TIL/PBMC配对样本 介入治疗他们的乳腺癌。这个样本库 目前包含来自80多名患者的临床材料。使用组合 分子和免疫组织化学技术，分解的肿瘤 对样本进行特定的TAA表达评估，并根据 分析了单个肿瘤、TIL和PBMC表达的TAA的嵌合体 针对这些特定抗原的免疫反应性的存在。 检测辅助性T细胞和前体CTL的方法(CTL/p) 这些活动构成了这些免疫学分析的基础。在以下方面的主要努力 第4年和第5年将集中完成分析。此外，a 直接给药的I期临床试验 金丝雀POX-MAGE-1/3微基因载体治疗伴有MAGE-1和/或 MAGE-3表达的肿瘤将在第3年中期开始，最有可能是携带 通过第四年和第五年的部分时间。尽管这一计划的主要目标是 试验的安全性和毒性，主要的实验室重点将放在 监测登记的患者的发展和增强反应 到特定的迷你族。以测量和量化为目的的分析 辅助性T细胞和CTL前体活动将成为 免疫学评估。总而言之，这些方法都是设计的 为了扩展我们目前对宿主响应的实用知识 自体乳腺肿瘤并利用这些发现制定 合理的、抗原特异性的、基于免疫的疗法。历年的研究 4和5将允许我们在第一阶段的上下文中测试这些概念 临床试验，并进一步为未来的试验奠定基础。