Hypoxia-Driven, Macrophage-Mediated Immunotherapy of Lung Cancer

Lung tumors contain not only the tumor cells, but also a variety of normal cells whose function is to help the lung tumor grow. One of these normal cells is an immune cell, known at the macrophage. An important function of macrophages (M0) is to kill tumor cells, but within lung tumors, this critical function is blocked due to inhibitory factors released within the tumor. One of these inhibitory factors, IL-IO, blocks the ability of macro phages to attack tumor cells and inhibits generation of immune responses that can effectively attack the tumor. Recent studies have shown that M0s in tumors of mice can be modified so that they can attack tumor cells and generate other anti-tumor immune responses. Importantly, these studies showed that a large percentage of the mice were cured of their tumors and continued to live tumor-free. Based on these observations, we propose to test a therapeutic model in mice with lung tumors to determine if this form of therapy can be adapted to the treatment of lung cancer. We will use bone marrow transplantation in which several genes are first inserted into the marrow cells before transplantation. The bone marrow cells will be induced to become M0s and then transplanted into mice with lung tumors, where they will travel to the lung tumor. The inserted genes will be turned on within the tumor where they will attack the tumor cells and help generate other immune responses that will also be able to kill the tumor cells. To be cel1ain that these immune responses will work effectively inside of the tumor, we will also treat the mice by injection of a drug to block the activity of the inhibitory factor, IL-IO. We will evaluate the effectiveness of this novel therapy by determining 1.) how efficiently the modified M0s travel to the tumor and activate their inserted genes; 2.) how effectively the immune system was able to generate immune responses against the tumor; 3.) whether mice can be cured of their lung tumors. The results of these studies will establish proof of principle for the potential of this novel form of lung cancer therapy to allow macrophages and other immune cells to attack lung tumor cells in tumor-bearing mice and to "cure" mice of their growing tumors.