The clinical strengths of
immunotherapy and small-molecule inhibitors targeting the
mitogen-activated protein kinase (MAPK) pathway appear to be largely complementary for the treatment of advanced
melanoma. In current practice, most patients with BRAF V600 mutant
melanomas will see both modalities. Several in vitro and in vivo studies suggest that combining
immunotherapy with MAPK inhibition may have synergistic effects. First, mouse models show that adoptive
cell therapy (ACT) can be enhanced by vaccination. Rapid
tumor destruction by
vemurafenib could provide a
vaccine-like stimulus to adoptively transferred T cells. Second, both in mice and in early clinical trials,
melanoma metastases treated with MAPK inhibitors seem to display increased T-cell infiltrates. Third, MAPK inhibition upregulates the expression of some
melanoma antigens and, therefore, may enhance T-cell recognition of
vemurafenib-treated
melanomas. Fourth,
vemurafenib may sensitize
tumor cells to immune destruction. Finally, some investigators have found that an optimal antitumor effect from MAPK inhibition is dependent on an intact host immune response. Currently, the Surgery Branch of the National Cancer Institute has initiated a phase II trial combining the BRAF inhibitor
vemurafenib with ACT using tumor-infiltrating lymphocytes in patients with BRAF-mutant
tumors to investigate the safety and efficacy of this combination. The proposed mechanisms for synergy between these two modalities can be complex, and their optimal combination may require testing a variety of sequences and schedules.