Malignant melanoma is characterized by a rapid progression, metastasis to regional lymph nodes and distant organs, and often resistance to chemotherapy and radiotherapy. According to the National Cancer Institute, it is estimated that 76,100 Americans will be newly diagnosed with melanoma and about 9,710 patients will die of the disease. Recent approval of YERVOY™ (ipilimumab, anti-CTLA-4) and Keytruda (pembrolizumab, anti-PD-1) by the US FDA marks the validation of immunotherapy for advanced metastatic melanoma patients, which has led to a renaissance in melanoma therapeutics using immunostimulatory monoclonal antibodies (mAbs) that enhance immune responses. These agents are including antagonists of immune-repressor molecules (e.g. CTLA-4 and PD-1) or agonists of immune-activating receptors (e.g. CD137, OX40 and CD40). Unfortunately, therapeutic benefit has been limited to a fraction of patients. This present project is searching for the resistance mechanisms underlying responsiveness to agonist mAbs directed against costimulatory molecule OX40 and development of novel combinatorial strategies. We have proposed an inhibitory role of a critical ecto-enzyme CD73 in the context of immunotherapies targeting immune costimulatory molecules. We hope to rapidly translate this knowledge into new combinatorial strategies using CD73 blockade for improving melanoma immunotherapy.
|Effective start/end date||5/1/15 → 10/30/17|
- Melanoma Research Alliance Foundation (AGMT ID#347520)