پیشرفت در ایمونوتراپی برای ملانوما Advances in Immunotherapy for Melanoma: A Comprehensive Review

1. Introduction Human melanomas are malignant tumors formed from melanocytes. As an aggressive type of skin cancer, melanoma is a major cause of morbidity and mortality. Notably, the incidence of melanoma is increasing worldwide, and no satisfactory treatments are currently available, with the exception of surgery [1–3]. The development of a melanoma is a dynamic process whereby the immune system not only protects against cancer development but also shapes the characteristics of the emerging tumors through a so-called “cancer-immunoediting” process. Accordingly, new immunotherapies are being investigated to identify and characterize the different subsets of cancer cells in melanoma in order to design individualized treatments for patients. Moreover, metastasis (Figure 1) [4] is a highly complex process, and its mechanisms have been difficult to elucidate in detail owing to the high genetic heterogeneity; nevertheless, the metastasis process is generally associated with severe immune tolerance, which is explained in part by the low percentages of tumor peptides or the poor immunogenicity of melanoma antigens [5]. To select the most effective therapy, the Cancer Genome Atlas Research (TCGA) network divided melanoma into four subtypes based on the presence of mutations in the BRAF, RAS, and neurofibromatosis type 1 (NF1) genes. Therefore, drugs targeting these genes have been developed as candidate treatments for melanoma. However, some tumors show resistance to BRAF inhibitor treatments, and some mechanisms for this drug resistance have been identified to contribute to treatment failure, which are caused by mutations in several genes in most cases [6, 7]. Accordingly, a promising treatment approach for patients with melanoma is combination therapy to simultaneously inhibit multiple pathways, including the BRAF (using vemurafenib or dabrafenib) and mitogen-activated protein kinase (MEK; using trametinib and cobemetinib) pathways, which produces a response in the majority of patients. Moreover, other agents that target the immune system are being actively investigated to improve the efficacy and reduce the toxicity of therapies to cure melanoma, such as the use of anticytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibodies (ipilimumab) and T cell immunoglobulin and mucin domain 3 (TIM3)/CD137 [8].