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.