DEXASOME BASED IMMUNOTHERAPY OF LUNG CANCER

基于地塞糖体的肺癌免疫治疗

• 批准号: 6294208
• 负责人: MICHAEL A MORSE
• 金额: $ 34.82万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-03-01 至 2003-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6294208
• 关键词: MHC class I antigen; clinical research; clinical trial phase I; cytotoxic T lymphocyte; enzyme linked immunosorbent assay; human subject; human therapy evaluation; metastasis; neoplasm /cancer immunology; neoplasm /cancer immunotherapy; nonsmall cell lung cancer; tumor antigens; vesicle /vacuole

The investigators propose a phase I/II clinical trial to explore the safety, feasibility, and clinical and immunologic activity of a potent, novel, and broadly applicable form of active immunotherapy: tumor antigen loaded autologous dexosomes. Dexosomes are vesicles released from dendritic cells that express the necessary Human Leukocyte Antigens (HLA), co-stimulatory, and adhesion molecules required to induce T cell immune responses. This proposed study would be the first clinical trial to test the hypothesis that peptide antigen loaded dexosomes will elicit antigen specific CD8+ T cell responses in patients with cancer. In animal models, tumor antigen loaded dexosomes induced immune responses that could protect against tumor challenge and cause tumor regression and were remarkably more potent than dendritic cells. In addition, because dexosomes represent cell free material, they have potential clinical advantages over dendritic cell-based immunotherapy, such as easier handling, storage and portability and no concerns about viability. One possible strategy to initially test the clinical and immunologic activity of dexosomes in patients is to target patients with advanced lung cancer. Because the prognosis for advanced lung cancer is poor, additional therapies such as immunotherapy warrant evaluation. Sixty-four percent of non-small cell lung adenocarcinomas express MAGE-3 or MAGE-4, and 80 percent of non-small cell squamous cell carcinomas express MAGE-3 or MAGE-4. HLA-A2 restricted peptide epitopes of both MAGE-3 and MAGE-4 that can be recognized by tumor antigen specific T cells have been identified. The applicants therefore propose to determine the safety and feasibility of generating and administering autologous dexosomes loaded with HLA-A2 restricted peptide epitopes of MAGE-3 and MAGE-4. The applicants propose to evaluate the clinical response and to analyze the MAGE-3 and MAGE-4 specific T cell response in patients with advanced lung cancers that express MAGE3 or MAGE4. This clinical trial will form the background for further trials designed to demonstrate both immunology and clinical benefits of dexosome-based immunotherapy.

研究人员提议进行一项I/II期临床试验，以探索 安全性、可行性、临床和免疫学活性， 新的、广泛应用的主动免疫治疗形式：肿瘤抗原 装载自体糊糖体。Dexosome是从树突状细胞释放出来的囊泡 表达必要的人类白细胞抗原(HL A)的细胞， 诱导T细胞免疫所需的共刺激分子和黏附分子 回应。这项拟议的研究将是第一次测试 多肽抗原负载的葡糖体将诱导抗原特异性的假说 肿瘤患者CD8+T细胞反应的研究在动物模型中，肿瘤抗原 负载糊糖体诱导的免疫反应可预防肿瘤 挑战和导致肿瘤消退的能力明显强于 树突状细胞。此外，因为糊糖体代表无细胞物质， 与树突状细胞相比，它们具有潜在的临床优势。 免疫疗法，例如更容易处理、储存和携带，而且不需要担心 关于生存能力。一种可能的策略是初步测试临床和 糊精在患者体内的免疫活性是以患者为靶点的 晚期肺癌。因为晚期肺癌的预后很差， 其他疗法，如免疫疗法，需要进行评估。六十四 80%的非小细胞肺腺癌表达MAGE-3或MAGE-4 百分比的非小细胞鳞癌表达MAGE-3或MAGE-4。 MAGE-3和MAGE-4的HLA-A2限制性多肽表位可以 被肿瘤抗原识别的特异性T细胞已经被鉴定出来。这个 因此，申请者建议确定以下项目的安全性和可行性 人类白细胞抗原A2限制性自体糊糖体的产生和给药 MAGE-3和MAGE-4的多肽表位。申请者建议评估 临床反应及MAGE-3、MAGE-4特异性T细胞应答分析 在表达MAGE3或MAGE4的晚期肺癌患者中。这 临床试验将构成进一步试验的背景，旨在 展示以糊精为基础的免疫学和临床益处 免疫疗法。