Immunotherapy with HD-IL-2 has produced durable benefit in 10% of patients with metastatic
      cutaneous melanoma. The antitumor activity of IL-2 has been limited at least in part by
      immunosuppressive and immune-regulatory forces within the tumor microenvironment. Antibodies
      against CTLA4 (e.g. ipilimumab), PD1 and its ligand (PD-L1) produced long-term benefit in
      approximately 20-40% of patients with advanced melanoma. In addition, the combination of
      ipilimumab with the anti-PD1 antibody, nivolumab, has shown tumor responses in up to 60% of
      patients with advanced melanoma. These findings have led to FDA approval of ipilimumab and
      nivolumab as an indication for treatment of patients with advanced melanoma and nivolumab for
      other cancers. While these data are exciting, only a few patients enrolled to the prior
      studies had metastatic MCM or ALM. There is no prospective immunotherapy studies conducted in
      MCM or ALM-specific population. Therefore the activity of the ipilimumab + nivolumab
      combination in these subsets or patients remains unknown

      Reliable predictive biomarkers for the use of immune checkpoint inhibitors are needed to
      identify pretreatment those patients most likely to respond and early on in treatment assays
      could help identify mechanisms of tumor response and resistance necessary to improve therapy.
      Although tumor PD-L1 expression in tumor confers higher treatment response rate, responses to
      nivolumab or nivolumab + ipilimumab alone were noted in 55% and 41% of patients,
      respectively, with PD-L1- tumors. Therefore, more reliable predictive biomarkers are needed.

      Recently, extensive studies on metastatic colorectal cancer have demonstrated that a new
      scoring system as well as density of immune cells infiltrates at the center of the tumor and
      its invasive margin, described as Immunoscore, could accurately separate a group of patients
      with high Immunoscore with improved DFS, and OS from those with low Immunoscore where the
      histopathological staging system cannot. A recent study has also demonstrated relationship
      between degree of pre-treatment CD8+ tumor infiltrating lymphocytes (TILs) infiltration and
      PD-L1 expression at the invasive margin of the advanced cutaneous melanoma and improved
      long-term clinical benefits in patients with advanced melanoma who received pembrolizumab
      monotherapy. Further, there appeared to be an association between tumor response and
      clonality of the immune infiltrate based on a next-generation sequencing method used to
      evaluate T-cell receptor rearrangement pre- and in response to checkpoint inhibitor therapy.
      Also, high mutational burden correlated with overall survival in patients with cutaneous
      melanoma treated with ipilimumab or lung cancer treated with anti-PD1. However, the biology
      of MCM and ALM are distinct from cutaneous melanoma at multiple levels. Consequently, the
      utility of predictive biomarkers developed for cutaneous melanoma remains unknown.