Raising the bar: optimizing combinations of targeted therapy and immunotherapy

Major breakthroughs have arisen in the treatment of melanoma and other cancers through the use of targeted and immunotherapy. Therapies targeting the BRAF^V600 mutation, such as vemurafenib and dabrafenib, were FDA-approved in 2011 and 2013, following demonstration of rapid, marked response in a majority of patients expressing the BRAF^V600 mutation and a survival benefit over then standard-of-care therapy with dacarbazine (1,2). However, the vast majority of responding patients eventually relapse, most often within only 6-12 months of treatment initiation (3,4). Another form of immunotherapy, immune checkpoint blockade, exploits a tumor-deployed immune escape mechanism through which tumors impede the immune response by binding checkpoint molecules which serve as brakes, specifically on T lymphocytes. Such therapies involving monoclonal blocking antibodies against cytotoxic T lymphocyte antigen-4 (CTLA-4) and programmed death-1 (PD-1) were approved in 2011 and 2014, respectively. Though these treatments are associated with responses in fewer patients (20-35%) (5,6) than treatment with targeted therapy, responses are often durable (7) with a significant proportion of patients achieving durable disease control. Unfortunately, many patients do not derive benefit from these forms of therapy (1,2,5,6), and more therapeutic options are needed. Another form of therapy that has been studied extensively is adoptive cell therapy (ACT), and involves the isolation and expansion of antigen-specific lymphocytes from tumor (tumor infiltrating lymphocytes-TIL) (8) or peripheral blood (9) from patients with melanoma (and other cancer types). This form of therapy is associated with responses in approximately 50% of metastatic melanoma patients (10), though its use has been limited by the technical expertise involved in isolation and expansion of these cells, as well as the infrastructure required for this therapeutic approach (11).