Combination immunotherapies for the treatment of melanoma

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DESCRIPTION (provided by applicant): Melanoma is the most common form of cancer in young adults1, and its incidence is rising at a rate higher than any of the seven most common cancers2, increasing 45% between 1992 and 20043. Plexxikon and Roche are codeveloping a BrafV600E inhibitor (i.e. PLX4032 (Vemurafenib)) and BMS/Medarex recently attained FDA approval for their anti-CTLA4 antibody (i.e. ipilimumab (Yervoy)). PLX4032 is a small molecule inhibitor of BrafV600E that induces rapid melanoma regression in the subset of patients that harbor this mutation4. BrafV600E inhibition provides promising early responses, but a combination therapy will undoubtedly be required for durable melanoma control. Immunotherapy is another approach that has recently demonstrated significant efficacy in patients with metastatic melanoma.6, 7 Ipilimumab has shown clear efficacy in clinical trials for metastatic melanoma however, only 11% of patients show partial or complete response, while posing significant challenges to clinicians due to associated toxicities. We have focused on targeting Plasmalemmal Vesicle Associated Protein-1 (Plvap/PV1), an endothelial specific protein with roles in angiogenesis8-10 and diapedesis of leukocytes11. PV1 is expressed on a subset of endothelia in normal tissues12-16. Importantly, PV1 is upregulated on the endothelium of most, if not all, human solid tumors, melanoma included8, 10, 17-19. In human glioblastomas, PV1 is among the top four most upregulated endothelial genes17, regulated by hypoxia8 and growth factors such as VEGF and HGF 8, 10, 19. Although PV1 is actively involved in pathological angiogenesis associated with tumor growth8-10, our preliminary data using PV1 gene knockouts show that PV1 in not required for normal tissue vasculogenesis or physiological angiogenesis, which is a particularly appealing feature of an anti-PV1 cancer therapy. Based on its association with tumor growth, we have investigated PV1 for its potential as a target for the therapy of cancer, especially melanoma. Data presented herein demonstrate that PV1 is expressed at high levels on endothelial cells associated with melanoma, and that anti-PV1 monoclonal antibodies delivered systemically effectively inhibit tumor growth in a genetic model of melanoma (Braf/Pten). PV1 an intriguing therapeutic target for solid tumors, especially in combination therapies that (1) directly target tumor cell proliferation and (2) stimulate anti-tumor immunity. To date, we have shown that systemic administration of anti-PV1 mAb confers a clear inhibition of melanoma growth in a murine melanoma model, on par with the efficacy of PLX4032. We plan to define the therapeutic window for anti-PV1 mAb when used in combination with state of the art therapies for melanoma and demonstrate synergistic efficacy of anti-PV1 combination therapies in a genetic murine melanoma model that closely mimics human disease.