The role of immunotherapy and molecular‑targeted therapy in the treatment of melanoma (Review)

Abstract

Skin melanomas are malignant neoplasms originating from neuroectodermal melanocytes. Compared to other neoplasms, melanomas have a high rate of growth. Their incidence is highest in Australia and New Zealand, in high-income European countries (Switzerland, Norway, Sweden) and in the US. In Poland, the standardized incidence rate is approximately 5/100,000. Melanomas are typically highly radioresistant and chemoresistant. Before the era of immunotherapy, inoperable lesions were treated using chemotherapy based mainly on dacarbazine, temozolomide or fotemustine, which did not yield the expected results in terms of extending survival time or improving patient comfort. Therefore, there has emerged a need to seek other solutions. In most cases, the use of immunological treatment or targeted therapy has had a positive impact on survival time and relapse-free survival. However, these periods are still relatively short, hence the need for further research and improvement of treatment. The most promising strategies appear to be antibodies that block programmed death receptor-1 (PD-1) and programmed death receptor ligand-1 (PD-L1) molecules, anti-CTLA4 antibodies (cytotoxic T-lymphocyte antigen 4) and therapy with BRAF and MEK inhibitors.

Outcomes of Patients with Metastatic Melanoma—A Single-Institution Retrospective Analysis

“…Interferon alfa (IFN-α) is a cytokine produced primarily by plasmacytoid dendritic cells as a result of stimulation of their TLR7 and TLR9 (Toll-like) receptors by cytokines. Binding of IFN-α to the receptor activated Janus-activated tyrosine kinase (JAK) results in an increase in immune system responses, inhibition of cell proliferation and stimulation of their differentiation [ 9 ]. The use of Intron A reduced the risk of recurrence by 17–18% ( p <0.0001), and meta-analyses showed an improvement in 5-year survival by approximately 3–5% [ 8 ].The patients benefiting most from the use of interferon in adjuvant treatment are patients with an ulcerated primary lesion, with micro-metastases in the sentinel node, but without macro-metastases to clinically enlarged lymph nodes [ 10 ].…”

“…Research on the immune response in cancer and on cellular signaling pathways has resulted in the introduction of a new generation of drugs into treatment. Currently, anti-PD-1 (nivolumab, pembrolizumab) and anti-CTLA4 (ipilimumab) antibodies are commonly used in the treatment of malignant melanoma [ 9 ].…”

“…The consequence of this activation is uncontrolled proliferation, escape from apoptosis and concomitantactivation of MEK-dependent angiogenesis by stimulation of HIF-1α (hypoxia inducible factor 1-alpha) and VEGF (vascular endothelial growth factor). BRAF inhibitors (vemurafenib, dabrafenib, encorafenib) and MEK inhibitors (trametinib, binimetinib, cobimetinib) are used in molecularly targeted treatment of melanoma [ 9 ].…”

“…Their introduction to therapy has reduced the role that chemotherapy and non-specific active immunotherapy (interferon, interleukin 2) plays in the treatment of patients with advanced melanoma [ 9 ]. These drugs are used both in adjuvant therapy and in the treatment of inoperable melanoma [ 9 ]. The use of new-generation drugs in adjuvant treatment reduced the risk of disease recurrence from about 51% to 25% [ 7 , 23 ].…”

“…Unfortunately, defining unambiguous criteria for the eligibility of patients for molecularly targeted therapy is extremely problematic, and, therefore, still constitutes a major challenge for modern medicine. Determining patient eligibility for modern treatment should be preceded by testing for the presence of changes in cellular metabolism or genetic profile, which may be a target for such treatment [ 9 ].…”