Uveal melanoma (UM) is the most common tumor of the eye in adults. In half of these patients, the disease turns fatal due to distant spread of the disease. Most commonly, patients will experience liver failure due to UM, which is terminal. Treatment for advanced stage UM may involve chemotherapy or liver-directed treatment such as radiation, hepatic infusion of drugs, or mechanical blocking of tumor vessels known as embolization. All of these approaches focus on killing the tumor directly, often with direct poisonous side effects for the patient. In recent years, immune therapy has come to the forefront of melanoma treatment. In contrast to other treatments, immune therapy focuses on educating or enhancing a patient's existing immune system against cancer so that it can seek out tumors in the body and control them. This new form of therapy comes with less severe side effects, and long-lasting tumor control in patients who are deemed ?responders.? Currently, we are unable to predict which patients will respond to immune therapy, and which patients will not. The goal of this project is to separate UM responders and non-responders by the immune signature present in their tumor before and during treatment with immune therapy. This will be accomplished by obtaining serial tumor biopsies and research blood collection on patients before and during the course of single-agent and combination immune therapy known as checkpoint blockade (ipilimumab, nivolumab, or pembrolizumab). Tumors will be analyzed for changes in T-cells, changes in protein expression related to immune cells, and RNA genomic changes related to immune system activation. Blood will be analyzed, similarly, for changes in immune system activation while receiving treatment, and correlated with clinical tumor response. Upon completion of this project, we expect to uncover the changes in a patient's blood and tumor that can predict response or lack of response to treatment with immune therapy. In patients with a lack of response, the identified immune signature will reveal resistance mechanisms and can be used to help us develop strategies to overcome resistance to immune therapy.
This project will uncover the unique immune signature of uveal melanoma tumors that respond to treatment with immune therapy as well as reveal the immune signature of non-responding tumors. The information gained from this work can be used to enhance responsiveness and overcome immune resistance in uveal melanoma patients and may be more broadly applicable to other tumor types with similar immune signatures.
|Li, Yiliang; Patel, Sapna Pradyuman; Roszik, Jason et al. (2018) Hypoxia-Driven Immunosuppressive Metabolites in the Tumor Microenvironment: New Approaches for Combinational Immunotherapy. Front Immunol 9:1591|