Metastatic cutaneous melanoma is featured by predominant resistance to conventional therapies, resulting in poor prognoses and almost uniformly high lethality due to this disease. About 60% of all melanoma clinical cases harbor the BrafV600E mutation, and most are responsive to the recently approved therapies that target the mutant Braf protein. However, disease generally recurs within 12-15 months displaying the acquires resistance to Braf inhibitors, aggressive growth and enhanced metastatic potential. Additional promising results that demonstrate the possibility of durable responses in a subset of patients have recently been achieved with immune checkpoint modulation therapy that targets PD1/PDL1 or CTLA4 or the combination, and further immunomodulation therapies are being developed. However, it is not clear why some patients respond so well, while others don't respond at all. In addition, it will be critical to determine dosing regimens, effective combinations of multiple immunotherapies and their combination with cancer cells or other components of the cancer stroma. The metastatic melanoma GDA models developed in this project has been demonstrated as a highly valuable preclinical resource in determining potential mechanisms of drug resistance and the development of effective combination treatments, dosing regimens and diagnostic strategies for evaluation in patients. The established and validated GDA models include HGF/MET-driven primary and metastatic melanoma, including models in which tumors express luciferase. In addition, primary Braf driven and primary and metastatic HGF/MET/Braf driven models have been established. These models have been actively employed during a broad-scope collaboration study aimed at a comparative assessment of the effects of checkpoint inhibitors in BRAF or HGF-driven mouse models of melanoma in collaboration with Dr. Glenn Merlino's CCR laboratory and a collaborating biotech company. These experiments achieved sustainable response to immune check point blockade in a fraction of experimental melanoma-bearing animals, as well as enable correlative studies linking therapeutic response with changes in the identity, intra-tumoral location, abundance and activation status of tumor infiltrating immune system cells. Several experiments have been also conducted to describe the changes to the tumor-infiltrating immune system composition and signatures in animals treated with different checkpoint inhibitor regimens. These data are currently being prepared for a publication.
