Ovarian cancer is the most deadly gynecologic malignancy. Approximately 80% of women are diagnosed with advanced staged disease with a 5-year survival of only 40%. Clearly, innovative and effective treatment options are needed for ovarian cancer. One of the reasons ovarian cancer is so lethal is because M2, or immunosuppressive macrophages, accumulate in and around the tumor, which promotes cancer growth and spread. Since macrophages are able to change back and forth between the M2 and M1, or pro-inflammatory type, converting tumor macrophages to the M1 type is an attractive method for treating ovarian cancer. To do this, we have already developed Macrophage Derived Engineered Vesicles (MEVs) from human macrophages. In our preliminary, in vitro data, we show (1) that our M1 MEVs are able to convert M2 macrophages into the M1 type, resulting in death of the ovarian cancer cells, and (2) that M1 MEVs specifically target tumors in mouse models. This suggests MEVs may be an effective and non-toxic treatment for ovarian cancer. The next step in developing MEVs as an anticancer agent is to perform a proof-of-concept animal study. Therefore, in this proposal, in the first 6 months, we will test the anticancer activity of MEVs in ovarian cancer animal models. If anticancer activity in animal models is similar to what we have observed in cell lines, we will move to the next step of development, which is to optimize MEVs as a therapeutic and comprehensively characterize MEVs to support the regulatory process for moving MEVs into human trials. Taken together, the overall objective of this proposal is to establish the in vivo activity of the first therapeutic strategy designed to re-train an individual’s own immune system to eradicate ovarian cancer and set the stage for human trials. Our team, with expertise in immunotherapy clinical trial design (Arnold), preclinical drug development (Kolesar), membrane biophysics (Richards), surgical oncology (Ueland), and immunology (Bondada), has a strong track-record of productive collaboration and is well qualified to carry out the proposed work.