Listeria Monocytogenes to Treat Hepatic Metastases

单核细胞增生李斯特菌治疗肝转移

• 批准号: 7085533
• 负责人: RICHARD D SCHULICK
• 金额: $ 31.53万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7085533
• 关键词: Listeria; Listeria infections; T lymphocyte; attenuated microorganism; colony stimulating factor; dendritic cells; flow cytometry; genetic strain; genetically modified animals; inflammation; laboratory mouse; leukocyte activation /transformation; liver neoplasms; metastasis; neoplasm /cancer immunotherapy; neoplasm /cancer vaccine; nonhuman therapy evaluation; tumor antigens; vaccine development; vaccine evaluation

DESCRIPTION (provided by applicant): In 2004, about 1,368,060 Americans were expected to develop cancer and 563,700 were expected to die, more than 1,500 people a day. Cancer is the second leading cause of death in the US, exceeded only by heart disease. In the US, 1 of every 4 deaths is from cancer. The National Institutes of Health estimate overall costs for cancer in the year 2003 at $189.5 billion. [1] Many cancers such as those originating in the digestive system have a very high propensity to develop hepatic metastases and the primary cause of morbidity and mortality in many cases is from the liver metastases. Digestive system cancer deaths are expected to account for 134,840 deaths in the US in 2004. Additionally, other cancer types such as respiratory system, breast, and skin cancers also develop hepatic metastases. Despite aggressive treatments with surgery, radiation, and chemotherapy, 41% of patients diagnosed with cancer will succumb to their disease. Immunotherapy has the potential to provide an alternative systemic treatment for many cancers. The specific aims of this research proposal are: Specific Aim 1: Define the mechanisms by which GM-CSF secreting tumor vaccines and infection with attenuated Listeria strains eliminate metastatic disease from the liver. Specific Aim 2: Identify an optimally attenuated strain of Listeria that has strong efficacy at targeting an immune response to the liver and that has low toxicity. Specific Aim 3: Use attenuated Listeria strains that have been genetically engineered to express relevant tumor antigens to further enhance the targeted immune response. Specific Aim 4: Define the role of dendritic cells in the priming and targeting of the immune response.

描述(申请人提供)：2004年，预计约有1,368,060名美国人罹患癌症，预计将有563,700人死亡，每天超过1,500人。癌症是美国第二大死因，仅次于心脏病。在美国，每4例死亡中就有1例死于癌症。美国国立卫生研究院估计，2003年癌症的总成本为1895亿美元。[1]许多癌症，如那些起源于消化系统的癌症，都有很高的肝转移倾向，在许多情况下，发病率和死亡率的主要原因是肝转移。预计2004年美国消化系统癌症死亡人数将达到134,840人。此外，其他类型的癌症，如呼吸系统癌、乳腺癌和皮肤癌也会发生肝转移。尽管通过手术、放疗和化疗进行积极的治疗，但41%的被诊断为癌症的患者会死于他们的疾病。免疫疗法有可能为许多癌症提供一种替代的全身治疗。 这项研究建议的具体目标是： 具体目标1：确定分泌GM-CSF的肿瘤疫苗和弱毒李斯特菌株感染消除肝脏转移疾病的机制。 具体目标2：确定一种最佳的减毒李斯特菌菌株，该菌株在针对肝脏的免疫反应方面具有很强的效力，并且毒性较低。 具体目标3：使用经过基因工程改造的减毒李斯特菌株表达相关的肿瘤抗原，以进一步增强靶向免疫应答。 具体目标4：确定树突状细胞在免疫反应的启动和靶向中的作用。