Project 3: Safety and Efficacy of Vemurafenib and High-Dose IFNα2b for Advanced Melanoma
John M. Kirkwood, MD (Clinical Translational Science)
Soldano Ferrone, MD, PhD (Basic Science)
Hassane Zarour, MD (Basic Science)
Ahmad A. Tarhini, MD, PhD
Hussein Tawbi, MD, PhD
Clinical evidence has convincingly shown that the BRAF inhibitors (BRAFi) like vemurafenib induce objective tumor regression in >50% of patients with metastatic melanoma that bear the V600E BRAF mutation. However, the tumor regressions are infrequently complete and disease progression occurs at a median of 6-7 months of treatment. Multiple mechanism(s) have been found to support the intrinsic and acquired resistance of melanoma cells to BRAFi and represent major limitations to the use of BRAFi as a single agent in patients with advanced melanoma. Therefore, it is now critical to define combinatorial strategies to eradicate BRAFi sensitive and resistant melanoma cells. In this project, we will test the hypothesis that BRAFi (vemurafenib) enhances the therapeutic efficacy of IFNα-2b in patients with metastatic melanoma. This hypothesis stems from our novel findings that BRAFi: 1) enhances the sensitivity of melanoma cells to IFNα-mediated anti-proliferative and proapoptotic activity; 2) increases T cell-mediated immune responses to melanoma cells by upregulating tumor antigen presentation and downregulating the expression of inhibitory receptor ligand by melanoma cells and; 3) prolongs the survival of melanoma-bearing mice. These findings reflect an increased IFNα-2b sensitivity of melanoma cells harboring BRAF mutations upon treatment with BRAFi.
To assess the clinical significance of our experimental data, the proposed Specific Aims will test the following hypotheses:
- The administration of BRAFi and IFNα-2b to patients with metastatic melanoma is safe, non-toxic and immunogenic;
- The administration of BRAFi enhances the antiproliferative and proapoptotic activity of IFNα-2b as well as its ability to upregulate the expression of HLA class I antigen presentation machinery (APM) component expression by melanoma cells and their recognition by T cells; and
- The administration of BRAFi and IFNα-2b increases tumor antigen (TA)-specific T cell expansion and function in the tumor microenvironment (TME) by decreasing PDL1 expression on melanoma cells and reducing tumor antigen load.
The information derived from the outlined studies will help to determine the therapeutic relevance of the BRAFi/IFNα-2b combination and the molecular mechanisms underlying the therapeutic effects of this combination.