A novel approach for treatment of ovarian cancer involves using enhanced immune cells such as genetically engineered T cells that are targeted to tumor specific proteins on ovarian cancer cells. T cells can be forced to express an artificial receptor termed a chimeric antigen receptor (CAR) that recognizes a specific foreign protein on ovarian cancer cells. We have generated a CAR+ T cells that eradicate ovarian cancers in mice that lack an immune system. However, despite the ability of CAR+ T cells to localize to tumor targets, their activation in the clinical setting can be inhibited by a suppressive tumor microenvironment. To this end, we have found that CAR+ T cells further modified to secrete hormones called IL-12 exhibit enhanced killing of ovarian tumor cells in the mouse. This is partly due to resistance to the suppressive tumor microenvironment in a clinically relevant mouse that has an immune system. Given these preclinical experimental outcomes, in this application we propose to assess the safety as well as the anti-tumor efficacy of CAR+ T cells in a phase I clinical trial treating patients with relapsed ovarian cancers. In order to further study the anti-tumor response of the CAR+ T cells, we will assess the persistence of CAR+ T cells in patients and characterize the response of the patient’s own immune system to the CAR+ T cells. Additionally, the tumor microenvironment will be examined pre- and post-injection of CAR+ T cells for changes in various immune factors.