The Effects of Treatment With Vemurafenib on the Immune System in Advanced Melanoma

Approximately 40-60 % of cutaneous melanomas select for a mutation in the BRAF protein which is part of a signaling pathway called the Mitogen Activated Protein Kinase (MAPK) pathway. Over 90% of mutations in BRAF occur at position V600 with the most common being a V600E mutation. Mutation at position V600 of BRAF activates the MAPK pathway which facilitates melanoma proliferation and growth. The response rate to treatment with vemurafenib in patients with stage IV melanoma expressing a V600E BRAF mutation is approximately 50%. A phase III study comparing first line treatment with vemurafenib compared to standard dacarbazine chemotherapy demonstrated a statistically significant overall survival benefit in this patient population. Based on this survival benefit vemurafenib was FDA approved for treatment of stage IV melanoma expressing a V600E BRAF mutation. Vemurafenib is administered at a dose of 960 milligrams orally twice daily.

While targeting BRAF can lead to survival benefits in patients with melanoma expressing BRAF mutation it is becoming increasingly apparent that the immune system is important in modulating the growth of melanoma. As such there are immune therapies FDA approved for the treatment of stage IV melanoma including ipilimumab which confers an overall survival benefit by activating the immune system through inhibition of the CTLA-4 protein expressed on certain T-cells. Little is known about how the exposure of different classes of immune cells to vemurafenib modulates the activity of the immune system. We do know that many melanomas express differentiation antigens which could potentially be recognized by the immune system. This recognition could potentially be utilized in the development of novel immunotherapeutic treatment approaches. The pharmacologic inhibition of the MAPK pathway does lead to increased expression of various melanoma differentiation antigens along with improved recognition by antigen-specific T-lymphocytes. Evaluation of a limited number of tumor biopsy specimens suggest that the infiltration of melanomas by CD4+ and CD8+ T-lymphocytes markedly increases following treatment with a BRAF inhibitor. Furthermore the viability and function (determined using assays for cytokine release assays and cytotoxic activity) of T-lymphocytes was not negatively affected by exposure to vemurafenib at concentrations known to cause anti-tumor effects.

The MAPK pathway is a pathway utilized by many cell types including immune cells and cells in the tumor microenvironment. As such vemurafenib could potentially modulate the activity of the MAPK pathway in the melanoma cells, immune cells, and components of the tumor microenvironment. Effects of vemurafenib on tumor cells may directly lead to changes in antigen presentation and effects on the innate and adaptive immune systems could potentially alter recognition of tumor cells and modulate positively or negatively immune recognition and antitumor activity. Therefore, a better understanding of immune modulation induced by anti-BRAF therapy should provide data to model and develop in a more rational fashion therapies which combine BRAF targeted and immune modulatory agents potentially using such agents as ipilimumab or anti-PD1 or anti-PDL1 antibodies.