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.

R01CA112160

2005-07-01

2010-04-30