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: 6203342
• 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/6203342
• 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中的研究基于以下假设： 癌症患者的细胞免疫反应虽然无效， 针对由其活跃生长的细胞表达的高度保守的TAA的反应 肿瘤，这些活动的特异性增强可能提供 改善宿主对肿瘤生长的控制。项目总体目标 因此，5是表征存在的潜在抗TAA反应性 在来自具有以下肿瘤的乳腺癌患者的TIL和PBMC群体中， 明确的TAA表达，并将这些临床前发现用作 构建合理的I期免疫治疗药物的框架 接近。前几年的科学努力，在接近 与核心4合作，重点是建立一个银行， 来自接受过外科手术的女性的配对肿瘤/Til/PBMC标本 干预治疗乳腺癌。这个标本库 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，解聚肿瘤， 评估标本的特异性TAA表达，并基于 分析由单个肿瘤、TIL和PBMC表达的TAA嵌合体 针对这些特定抗原的免疫反应性的存在。 旨在检测辅助性T细胞和前体CTL（CTL/p）的试验 活性形成这些免疫学分析的基础。主要努力 第4年和第5年将专注于完成分析。另外还有按 I期临床试验涉及直接施用重组 金丝雀痘病毒-法师-1/3小基因载体对具有法师-1的HLA-A1患者和/或 表达法师-3的肿瘤将在第3年中期开始开始，并且很可能携带 到第四年和第五年的部分时间。虽然主要目标是 试验是安全性和毒性，主要的实验室重点将放在 监测入组患者的反应发展和增强 到特定的小基因。旨在测量和定量的试验 辅助性T细胞和CTL前体活动将作为 免疫学评估。总体而言，这些方法旨在 扩大我们目前对宿主反应的工作知识， 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。年的研究 4&5将允许我们在第一阶段的背景下测试这些概念 临床试验，并进一步为未来的试验奠定基础。