GENETIC IMMUNOTHERAPY FOR LUNG CANCER

肺癌的基因免疫治疗

• 批准号: 6750063
• 负责人: Steven M. Dubinett
• 金额: $ 27.45万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-01-01 至 2006-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6750063
• 关键词: Adenoviridae; CD4 molecule; CD8 molecule; dendritic cells; enzyme linked immunosorbent assay; gene targeting; genetically modified animals; histocompatibility antigens; interferon gamma; interleukin 7; laboratory mouse; lung neoplasms; neoplasm /cancer immunotherapy; neutralizing antibody; nonhuman therapy evaluation; transfection /expression vector; tumor antigens

DESCRIPTION: (Applicant's Abstract) The applicant's efforts to produce an effective cancer therapy are focused on methods to restore tumor antigen presentation. Dendritic cells (DC) are bone marrow-derived leukocytes characterized by the high level expression of major histocompatibility (MHC) and co-stimulatory molecules as well as the capacity of take-up, process and present antigens. These powerful capacities facilitate activation and expansion of antigen-specific T cells. Recent murine studies and clinical trials have shown that DC, when appropriately armed with a tumor antigen (Ag) can promote antitumor immunity and significant tumor regression. In this application the applicant hypothesizes that autologous DC, when transduced with an adenoviral vector expressing the IL-7 gene (DC-AdIL-7), can be used to stimulate specific and therapeutic anti-tumor immunity without the need for priming with a tumor antigen ex vivo. In preliminary studies, the intratumoral injection of these gene-modified DC into established murine tumors induced specific antitumor response both locally and at metastatic sites. Animals treated in this manner not only experienced complete tumor regression, but also were protected from subsequent tumor challenge. He hypothesizes that the autologous tumor provides access to the entire repertoire of available antigens, both increasing the likelihood of a response and reducing the potential for phenotypic modulation. The overall goal of this application is to use murine models to determine the immunologic mechanisms by which DC-AdIL-7 mediate tumor eradication. The specific aims are: 1) to identify the mechanisms of antitumor responses in DC-AdIL-7 intratumoral therapy and 2) to determine the features of transferred DC effective antitumor response. A unique focus of this work is the emphasis on a DC-based approach to stimulate specific immune responses that does not exclude patients on the basis of HLA phenotype or because of lack of expression of a particular tumor antigen. Thus, this therapy would be available to all lung cancer patients in the appropriate clinical setting. He anticipates that the studies described in the current application will enhance our understanding of the complex interactions between tumor cells and DC and thus lead to more effective therapy for lung cancer. His priority is to determine the mechanisms of antitumor responses in DC-AdIL-7 intratumoral therapy and the features of transferred DC responsible for mediating an effective antitumor response. Elucidation of the antitumor pathways in this model will ultimately allow him to define optimal conditions for therapeutic application of intratumoral DC-AdIL-7.

描述：(申请人摘要)申请人为提交一份 有效的癌症治疗集中在恢复肿瘤抗原的方法上 演示文稿。树突状细胞(DC)是一种骨髓源性白细胞 以主要组织相容性(MHC)的高水平表达为特征 和共刺激分子，以及摄取、加工和 现在的抗原。这些强大的功能便于激活和扩展 抗原特异性T细胞。最近的小鼠研究和临床试验表明 研究表明，当适当地武装肿瘤抗原(Ag)时，DC可以促进 抗肿瘤免疫和显著的肿瘤消退。在此应用程序中， 申请人假设自体DC在用腺病毒转导时 表达IL-7基因的载体(DC-ADIL-7)可用于刺激特异性 和治疗性抗肿瘤免疫，而不需要用肿瘤引发 体外抗原。在初步研究中，这些药物的瘤内注射 基因修饰树突状细胞诱导特异性抗肿瘤作用的研究 局部和转移部位的反应。以这种方式对待的动物 不仅经历了肿瘤的完全消退，而且还受到了保护 随后的肿瘤挑战。他假设自体肿瘤提供了 访问整个可用抗原库，既增加了 反应的可能性和降低表型调节的可能性。 该应用程序的总体目标是使用小鼠模型来确定 DC-ADIL-7介导肿瘤清除的免疫学机制。这个 具体目标是：1)确定抗肿瘤反应的机制 DC-ADIL-7瘤内治疗和2)确定转移的特点 DC有效的抗肿瘤作用。这项工作的一个独特的重点是强调 一种基于DC的方法来刺激特定的免疫反应，而不是 排除基于人类白细胞抗原表型或缺乏表达的患者 一种特定的肿瘤抗原。因此，这种疗法将适用于所有人。 肺癌患者在适当的临床环境下。他预料到 目前申请中描述的研究将增进我们的理解 肿瘤细胞和DC之间的复杂相互作用，从而导致更多 肺癌的有效治疗。他的首要任务是确定机制 DC-ADIL-7瘤内治疗的抗肿瘤反应及特点 转移的DC负责调节有效的抗肿瘤反应。 阐明这个模型中的抗肿瘤途径最终将使他 确定瘤内治疗应用的最佳条件 DC-ADIL-7