IL-12 Gene Therapy for Metastatic Osteosarcoma

IL-12 基因治疗转移性骨肉瘤

• 批准号: 7024595
• 负责人: LAURA L WORTH
• 金额: $ 13.61万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-11 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7024595
• 关键词: T cell receptor; antigen presentation; athymic mouse; biotechnology; cell growth regulation; cell migration; clinical research; cytotoxic T lymphocyte; dendrites; gene delivery system; gene therapy; helper T lymphocyte; immunocytochemistry; inhalation drug administration; interferon gamma; interleukin 12; intravenous administration; leukocyte activation /transformation; lung neoplasms; macrophage; metastasis; natural killer cells; neoplasm /cancer immunotherapy; nonhuman therapy evaluation; osteosarcoma

DESCRIPTION (provided by applicant): Osteosarcoma is the most common primary bone malignancy that usually presents during the adolescent and young adult years when the long bones are undergoing rapid growth. At diagnosis children with osteosarcoma frequently have pulmonary micrometastases that are not detected by chest X ray or CT. Despite aggressive chemotherapy and surgical intervention, 30-40% of patients will relapse with pulmonary metastases. The 2-year disease-free survival has not changed significantly in the past 15 years. New agents and novel approaches are needed to increase the survival rate in these children. Using a nude mouse model with human osteosarcoma lung metastases, intranasal therapy with an adenoviral vector expressing interleukin-12 resulted in a dramatic decrease in the number and size of pulmonary metastases in mice. The antitumor immunity induced by this therapy is mediated primary by natural killer cells and antiangiogenic mechanisms. IL-12 has two main anti-tumor activities that are immune-dependent and immune-independent. The nude mouse model is useful for determining the immune-independent mechanisms. Recently an orthotopic, syngenic murine osteosarcoma model was developed. After the intraosseous injection of murine tumor cells, a tumor forms in bone at the site of injection. These mice go on to spontaneously develop pulmonary metastases. This model, with an intact immune system, will allow the immune-dependent mechanisms of IL-12's antitumor activity to be determined. Four specific aims will be pursued: 1) To determine the identity and timing of cells that infiltrate tumor cells after the administration of Ad.mIL-12. 2) To determine if IL-12 activates NK cells to eradicate pulmonary osteosarcoma metastases. 3) To determine the role IL-12 (the primary inducer of interferon-?) plays in stimulating macrophage and dendritic activity. 4) To determine the role T cells play in the anti-tumor activity of gene therapy with IL-12. Successful completion of these studies will result in a better understanding of the role the immune system (when activated with IL-12 and T cells receptor agonists).

描述（由申请人提供）：骨肉瘤是最常见的原发性骨恶性肿瘤，通常出现在长骨快速生长的青少年和青年时期。 骨肉瘤儿童在诊断时经常出现胸部 X 光或 CT 无法检测到的肺部微转移。 尽管进行了积极的化疗和手术干预，30-40%的患者仍会出现肺转移复发。 2年无病生存率在过去15年中没有显着变化。 需要新的药物和新的方法来提高这些儿童的存活率。 使用具有人骨肉瘤肺转移的裸鼠模型，用表达白细胞介素12的腺病毒载体进行鼻内治疗，导致小鼠肺转移的数量和大小显着减少。 这种疗法诱导的抗肿瘤免疫主要由自然杀伤细胞和抗血管生成机制介导。 IL-12有两种主要的抗肿瘤活性，即免疫依赖性和免疫非依赖性。 裸鼠模型可用于确定免疫独立机制。 最近开发了一种原位同基因鼠骨肉瘤模型。 骨内注射小鼠肿瘤细胞后，注射部位的骨中会形成肿瘤。 这些小鼠继续自发地发生肺转移。 该模型具有完整的免疫系统，将能够确定 IL-12 抗肿瘤活性的免疫依赖性机制。 将追求四个具体目标：1) 确定在施用 Ad.mIL-12 后浸润肿瘤细胞的细胞的身份和时间。 2) 确定IL-12是否激活NK细胞以根除肺骨肉瘤转移。 3) 确定IL-12（干扰素-？的主要诱导剂）在刺激巨噬细胞和树突状活性中的作用。 4) 确定T细胞在IL-12基因治疗的抗肿瘤活性中所起的作用。 成功完成这些研究将有助于更好地了解免疫系统（当用 IL-12 和 T 细胞受体激动剂激活时）的作用。