Immunotherapy in the Treatment of Metastatic Melanoma: Current Knowledge and Future Directions

Abstract

Melanoma is one of the most immunologic malignancies based on its higher prevalence in immune-compromised patients, the evidence of brisk lymphocytic infiltrates in both primary tumors and metastases, the documented recognition of melanoma antigens by tumor-infiltrating T lymphocytes and, most important, evidence that melanoma responds to immunotherapy. The use of immunotherapy in the treatment of metastatic melanoma is a relatively late discovery for this malignancy. Recent studies have shown a significantly higher success rate with combination of immunotherapy and chemotherapy, radiotherapy, or targeted molecular therapy. Immunotherapy is associated to a panel of dysimmune toxicities called immune-related adverse events that can affect one or more organs and may limit its use. Future directions in the treatment of metastatic melanoma include immunotherapy with anti-PD1 antibodies or targeted therapy with BRAF and MEK inhibitors.

Current molecular and clinical insights into uveal melanoma (Review)

“…Several chemotherapeutic drugs, including dacarbazine, cisplatin, trosulfan, temozolomide and fotemustine, have been investigated, exhibiting a low response rate and disappointing outcomes ( 114 , 147 ). While immunotherapy has noticeably improved outcomes in metastatic cutaneous melanoma, this has not been the case for metastatic UM ( 148 ). A possible reason for such a different response to immunotherapy could be related to the different biological characteristics between cutaneous and UMs, as well as their different immunogenicity ( 149 , 150 ).…”

Advances in Targeting Cutaneous Melanoma

“…Recently, a randomized placebo-controlled study in stage III patients with CM demonstrated that adjuvant ipilimumab increases relapse-free survival (RFS) and OS. Nevertheless, more than half of patients developed severe side effects (grade 3 or 4) with ipilimumab, and five patients (1.1%) even had a grade 5 outcome [ 23 , 24 , 25 , 26 , 27 ]. As a result of ipilimumab-induced T cell activation, a variety of immune-mediated adverse effects (irAEs) have been observed, particularly including colitis, skin rashes, hepatitis, and less frequently hypophysitis.…”

“…Two studies demonstrated that the combination of nivolumab plus ipilimumab (ORR: 56.7%) resulted in higher clinical benefit when compared to -nivolumab (ORR: 43.7%) or mono-ipilimumab (ORR: 19%). Five-year OS rates were 52% in the combined treatment arm, 44% in the mono-nivolumab arm, and 26% in the mono-ipilimumab arm [ 26 , 27 , 28 , 29 ]. In 2015, the combination of nivolumab plus ipilimumab was approved based on positive ORR and PFS data.…”

“…Combination therapies are associated with much higher rates of irAEs, which are justified by long-term disease response. However, the subgroup of patients who might benefit from the combination is not known prior to therapy, potentially exposing patients to unnecessary toxicity [ 25 , 26 , 27 , 28 , 29 , 30 , 31 ]. Brain metastases are a common cause of disabling neurologic complications and poor prognosis in CM patients.…”

Discovery of immunogenic cell death-inducing ruthenium-based photosensitizers for anticancer photodynamic therapy

“…2 Next, we evaluated the immunological repercussions for cell death within melanoma cells following Ru PDT. 2 Considering the positive correlation between antitumor immunity and better melanoma outcomes, 3,4 we specifically investigated a phenomenon of immunogenic cell death (ICD) within Ru PDT-treated melanoma cells. In the context of cancers, ICD is a regulated form of cell death that encompasses a cascade of immune responses 5,6 promoting adjuvanticity and antigenicity -both essential for the development of antitumor immunity.…”