Listeria Monocytogenes to Treat Hepatic Metastases

2004年，预计约有1，368，060名美国人患上癌症，563，700人预计死亡，每天超过1，500人。癌症是美国第二大死亡原因，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，如起源于消化系统的癌症，具有非常高的发展肝转移的倾向，并且在许多情况下发病率和死亡率的主要原因是来自肝转移。2004年美国消化系统癌症死亡人数预计为134，840人。此外，其他癌症类型，如呼吸系统，乳腺癌和皮肤癌也会发生肝转移。尽管有手术、放疗和化疗等积极治疗，但41%的癌症患者仍会死于疾病。免疫疗法有可能为许多癌症提供替代的全身治疗。 这项研究建议的具体目标是： 具体目标1：定义分泌GM-CSF的肿瘤疫苗和减毒李斯特菌菌株感染消除肝脏转移性疾病的机制。 具体目标二：确定一种最佳减毒的李斯特菌菌株，该菌株在靶向肝脏免疫反应方面具有很强的效力，并且毒性低。 具体目标3：使用经过基因工程改造的减毒李斯特菌菌株表达相关肿瘤抗原，以进一步增强靶向免疫反应。 具体目标4：确定树突状细胞在免疫应答的引发和靶向中的作用。

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.